@article {pmid40568677,
year = {2025},
author = {Shade, LM and Sharifitabar, M and Beiser, A and Satizabal, CL and Mosley, TH and Curran, JE and Bressler, J and Heckbert, SR and Hughes, TM and Austin, TR and Nasrallah, IM and Launer, LJ and Yanek, LR and Bis, JC and Doddapaneni, H and Gibbs, RA and Gabriel, S and Gupta, N and Viaud-Martinez, KA and Smith, AV and Opsasnick, LA and Ammous, F and Smith, JA and Arnett, DK and Kardia, SLR and Psaty, BM and Longstreth, WT and Mathias, RA and Nyquist, P and Rich, SS and Rotter, JI and Boerwinkle, E and DeCarli, CS and Glahn, DC and Blangero, J and Fornage, M and Fardo, DW and Seshadri, S and Sarnowski, C},
title = {Whole genome sequence association analysis of brain structural volume measures in the NHLBI TOPMed Program highlights novel loci in diverse participants.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.11.25329426},
pmid = {40568677},
abstract = {Brain structural volumes are highly heritable and are linked to multiple neuropsychological outcomes, including Alzheimer's disease (AD). Genome-wide association studies have successfully identified genetic variants associated with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), and lateral ventricular volume (LVV). However, these studies mostly focused on common genetic variants with minor allele frequencies (MAF) > 1%, and individuals included in most of these studies were of predominantly European ancestry. Here, we performed whole-genome sequence (WGS) association studies of MRI brain volumes in 7,674 individuals of diverse race and ethnicity from the Trans-Omics for Precision Medicine (TOPMed) program. We identified novel genetic loci on chromosomes 13 and 16 near LINC00598 and CACNG3 associated with HV and TBV, respectively (lead variants rs115674829, P -value = 1.7×10 [-9] in pooled analysis and rs150440001, P -value = 6.6×10 [-9] in black participants). Both lead variant minor A alleles are rarer in white participants (MAF = 0.14% and 0.03%) and in Hispanic participants (MAF = 1.5% and 0.17%) but more common in black participants (MAF = 13% and 1.5%). Rare variant aggregated analyses identified RIPK1, a gene encoding a kinase involved in neuroinflammation and promising target for AD treatment, suggestively associated with LVV (P -value=5×10 [-6]). This study provides new insights into the genetic correlates of brain structural volumes and illustrates the importance of leveraging WGS data and cohorts of diverse race and ethnicity to better characterize the genetic architecture of complex polygenic traits.},
}

@article {pmid40568661,
year = {2025},
author = {Mansel, CO and Ghisays, V and Mahnken, JD and Swerdlow, RH and Reiman, EM and Karnes, JH and Denny, JC and Veatch, OJ},
title = {Downward bias in the association between APOE and Alzheimer's Disease using prevalent and by-proxy disease sampling in the All of Us Research Program.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.22.25328175},
pmid = {40568661},
abstract = {BACKGROUND: Recent genome-wide association studies (GWAS) for Alzheimer's Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by 1) including non-age-matched controls and prevalent cases, and/or 2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example.

METHODS: Participants in the All of Us Research Program over the age of 49 at enrollment (n=258,693) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). Dementia diagnoses were determined using available Electronic Health Records (EHR) and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression.

RESULTS: The mean age of the cohort was 67±10 years, and it was 58% female; 63% clustered predominantly with European genetic reference populations. Among the participants, 3,107 (1.2%) had prevalent ADRD, 301 (0.1%) had incident ADRD, and 19,910 (7.7%) reported a family history of ADRD (proxy ADRD). Both prevalent and proxy ADRD had attenuated associations with APOE genotype compared to incident ADRD. The adjusted generalized ratio (95% CI) (AGR) for incident ADRD for APOE ε4 heterozygotes was 2.95 (2.31-3.74) compared to 2.10 (1.96-2.24) and 1.42 (1.32-1.55) for proxy and prevalent ADRD, respectively. For APOE ε4 homozygotes, the effect sizes were even more different. Furthermore, APOE association effect sizes increased when restricting the control (no ADRD) group to older age brackets.

CONCLUSIONS: Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like All of Us , with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.},
}

@article {pmid40568182,
year = {2025},
author = {Maboudi, M and Soleymani, E and Banimostafavi, ES and Kordi, S and Adelani, M and Zakariaei, Z and Fakhar, M},
title = {Coexistence of Tuberculosis and Lophomoniasis in a Patient With Alzheimer's Disease.},
journal = {Respirology case reports},
volume = {13},
number = {6},
pages = {e70248},
pmid = {40568182},
issn = {2051-3380},
abstract = {The coexistence of lophomoniasis and tuberculosis (TB), both airborne diseases, is relatively uncommon. Co-infections like these can complicate treatment strategies due to overlapping symptoms and potential drug interactions. We report a rare case of comorbidity involving two pulmonary diseases, lophomoniasis and TB, in an 82-year-old woman with Alzheimer's disease (AD) from northern Iran. Her primary symptoms included weakness, lethargy, dyspnea, sputum production, night sweats, and significant weight loss. Both TB and lophomoniasis can compromise the immune system, potentially worsening the progression or severity of AD by increasing susceptibility to infections or enhancing neuroinflammation. Following the prescription of appropriate drug regimens for both diseases, the patient was discharged from the hospital in stable condition. Overall, it is crucial to consider lophomoniasis in the differential diagnosis of patients with pulmonary tuberculosis, especially in endemic areas where both infections are prevalent, to ensure timely diagnosis and effective management.},
}

@article {pmid40568106,
year = {2025},
author = {Xiao, L and Sharma, P and Yang, X and Abebe, D and Loh, YP},
title = {Neurotrophic Factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's Disease mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.04.657876},
pmid = {40568106},
issn = {2692-8205},
abstract = {BACKGROUND: The global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic Factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology AD mouse models However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.

METHODS: AAV-human NF-α1/CPE and a non-enzymatic form, NF-α1/CPE -E342Q were delivered into hippocampus of 3xTg-AD mice and effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of hippocampus of 3xTg-AD mice with and without AAV-NF-α1/CPE treatment was carried out.

RESULTS: Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and increase in activated microglia in 3xTg-AD mice, indicating its action is independent of its enzymatic activity. Quantitative proteomic analysis of hippocampus of 3xTg-AD mice that underwent NF-α1/CPE gene therapy revealed differential expression of >2000 proteins involving many metabolic pathways. Of these, two new proteins down-regulated by NF-α1/CPE: Nexin4 (SNX4) and Trim28 which increase Aβ production and tau levels, respectively were identified. Western blot analysis verified that they were reduced in AAV-NF-α1/CPE treated 3xTg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as top signaling pathway altered as a response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3xTg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple proteins known to be markers of autophagy were down-regulated in 3xTg-AD mice, accounting for impaired autophagy. Expression of these proteins were upregulated in 3xTg-AD mice with NF-α1/CPE gene therapy, thereby reversing autophagic impairment.

CONCLUSIONS: This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3xTg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment.},
}

@article {pmid40567814,
year = {2025},
author = {Du, L and Li, G and Wei, Y and Han, G},
title = {γ-secretase targeting in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251349529},
pmid = {40567814},
issn = {2542-4823},
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and is characterized by memory loss and cognitive decline. The amyloid cascade hypothesis posits that the pathogenesis of AD is initiated by the oligomerization and accumulation of toxic amyloid-β (Aβ) peptides within the brain. The aspartic protease γ-secretase, which catalyzes the final step in the cellular production of Aβ peptides, has been identified as a potential target for anti-amyloid intervention strategies. This target has attracted increasing attention in recent years, and novel small molecules have been developed as selective γ-secretase inhibitors and γ-secretase modulators. This review aims to discuss the role of γ-secretase protein hydrolysis activity in the pathogenesis of AD and to review the molecular mechanisms and prospects for the future development of strategies that target γ-secretase to intervene in AD development, which is expected to provide new ideas for the treatment of AD.},
}

@article {pmid40567363,
year = {2025},
author = {Adnan, M and Siddiqui, AJ and Bardakci, F and Surti, M and Badraoui, R and Patel, M},
title = {Neuroprotective potential of quercetin in Alzheimer's disease: targeting oxidative stress, mitochondrial dysfunction, and amyloid-β aggregation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1593264},
pmid = {40567363},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) peptide accumulation, oxidative stress, mitochondrial dysfunction and cholinergic deficits, all of which contribute to neuronal damage and cognitive decline.

METHODS: This study investigated the neuroprotective potential of quercetin, a natural flavonoid, in human neuroblastoma SH-SY5Y cells exposed to Aβ-induced toxicity. Various assays were conducted to evaluate cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), acetylcholinesterase (AChE) activity and Aβ aggregation.

RESULTS: Quercetin significantly enhanced cell viability and reduced oxidative stress by lowering intracellular ROS levels. It preserved mitochondrial integrity by stabilizing ΔΨm and inhibited AChE activity, thereby supporting cholinergic function. Additionally, quercetin reduced Aβ aggregation and the formation of toxic amyloid fibrils.

DISCUSSION: These findings suggest that quercetin confers neuroprotection by targeting multiple pathological mechanisms involved in AD, including oxidative stress, mitochondrial dysfunction, AChE activity and Aβ aggregation. Quercetin demonstrates promise as a natural therapeutic agent for the treatment of AD. However, further in-vivo investigations and clinical studies are warranted to validate these findings and explore its translational potential.},
}

@article {pmid40567106,
year = {2025},
author = {Popp, ZT and Ang, TFA and Hwang, PH and Au, R and Chen, J},
title = {Association between education and rate of cognitive decline among individuals with Alzheimer's disease: A multi-national European observational study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352216},
doi = {10.1177/13872877251352216},
pmid = {40567106},
issn = {1875-8908},
abstract = {BackgroundThe cognitive reserve (CR) hypothesis presumes higher tolerance of Alzheimer's disease (AD)-related pathology without functional decline for those with high education and more rapid decline after AD onset. Evidence supporting the second part of the hypothesis has been largely confined to U.S.-based studies.ObjectiveTo assess the relationship between education and cognitive decline in a multi-national European cohort of older adults living with AD.MethodsWe analyzed data from participants recruited into the GERAS-EU cohort study from AD clinics in the United Kingdom, Germany, and France. Linear mixed models were employed to assess the relationship between education (dichotomized using a 12-year cutoff) and cognitive decline measured by Mini-Mental State Examination (MMSE) scores during 1.5 to 3 years of follow-up, adjusting for age, sex, time from formal diagnosis, country, comorbidities, and AD treatment.ResultsA total of 1313 participants were analyzed, with mean age of 77.3 years (SD = 7.6), 715 (54.5%) females, and 378 (28.8%) with high education (≥12 years). Participants with high education experienced a 0.19-point greater decline (versus low education group) in MMSE scores every 6 months during follow-up (95% Confidence Interval: 0.03-0.35, p = 0.02). The secondary analyses (stratified by disease severity, sex, or country) showed a consistent direction of the association, although only significant in the severe AD group (p = 0.01).ConclusionsOur findings provide partial support for the CR hypothesis. Delayed AD diagnosis in individuals with high education may contribute to faster decline after diagnosis, highlighting the importance of sensitive screening for early signs of cognitive impairment.},
}

@article {pmid40566876,
year = {2025},
author = {Greenaway, AM and Hwang, F and Nasuto, S and Ho, AK},
title = {Home-Based Attentional Bias Modification with Webcam-Based Eye Tracking with Persons with Cognitive Impairment: A Feasibility Study.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/07317115.2025.2523049},
pmid = {40566876},
issn = {1545-2301},
abstract = {OBJECTIVES: Remotely delivered attentional bias modification (ABM) studies involving persons with cognitive impairment are lacking. Thus, the feasibility of an adapted ABM paradigm with webcam-based eye tracking was explored.

METHODS: Four of the eight participants recruited (males, Mage = 69 years, Alzheimer's disease = 3, mild cognitive impairment = 1) completed up to four daily ABM sessions. Tasks comprised pre- and post-intervention depression (PHQ-9), anxiety (GAD-7), and rumination (RRS) measures, a cognitive screen (TICS) (A), affect (PANAS) (B) and dot-probe AB measures (C), and dot-probe ABM (D) (Session 1-A, B, C, D, C, and B; Sessions 2 to 4-B, D, C, and B).

RESULTS: The intervention was feasible (as defined by completion rates) and appeared beneficial in this small sample (as defined by post-intervention improvements in mood). Sessions were long, and task completion/adherence was impacted by task access/participants' ability to complete tasks independently. Mind wandering, stimuli familiarity, and eye/fatigue were reported.

CONCLUSIONS: The intervention requires further adaptation (e.g. fewer eye-tracking tasks per session). Limitations include participant self-selection/loss, a lack of control group, and that the determinants of mood change are unclear.

CLINICAL IMPLICATIONS: ABM, a novel intervention, may be an effective mood-disorder treatment for individuals with cognitive impairment.},
}

@article {pmid40566858,
year = {2025},
author = {Carlisle, TC and Bateman, JR and Yang, Y and Lachner, C and Stockbridge, MD and Flashman, LA and Chemali, Z and Alzbeidi, N and Pressman, PS and Osibajo, AM and Bobrin, BD and Martinez-Menendez, CJ and Teixeira, AL and Daffner, KR and , },
title = {Antiamyloid Monoclonal Antibodies in Alzheimer's Disease Part 2: Challenges in Dementia Care Delivery System Logistics.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20240203},
doi = {10.1176/appi.neuropsych.20240203},
pmid = {40566858},
issn = {1545-7222},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative illness affecting nearly 7 million people in the United States. Until 2023, no disease-targeting pharmacotherapeutics were widely available outside of research studies. With relatively recent regulatory approval and increasing availability of antiamyloid therapies (AATs) in the United States, management of AD is rapidly shifting from symptomatic and supportive care alone to treatments aimed at disease modification. Appropriate selection of patients for AATs can be challenging and varies among health care settings and systems despite published appropriate-use recommendations. The first of this two-part Treatment in Behavioral Neurology & Neuropsychiatry series from the American Neuropsychiatric Association Dementia Special Interest Group addresses the challenges with patient selection. In this second part, the authors offer dementia-focused health care vignettes to illustrate challenges with AAT delivery encountered in different settings and discuss emerging logistical issues associated with delivery of dementia-focused care based on AAT protocols.},
}

@article {pmid40566818,
year = {2025},
author = {Smail, SW and Kheder, AH and Mustafa, HK and Abdulqadir, SZ and Jalal, KF and Yashooa, RK and Ghayour, MB and Abdolmaleki, A and Shekha, MS},
title = {Kenpaullone attenuates amyloid-beta deposition and neuroinflammation, improving memory in a 5XFAD mouse model of Alzheimer's disease.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01616412.2025.2520983},
pmid = {40566818},
issn = {1743-1328},
abstract = {Kenpaullone is known for its neuroprotective and anti-inflammatory properties. We explored the potential of a specific intervention to influence cognitive abilities and disease-related brain changes in a mice model replicating key aspects of Alzheimer's disease (AD). We employed 5XFAD transgenic mice, which develop Aβ plaques and cognitive impairments that mirror those observed in individuals with Alzheimer's disease (AD). The animals were treated with Kenpaullone (1 mg/kg, 3 mg/kg, and 5 mg/kg) or a vehicle (DMSO). The study evaluated memory using the Morris water maze (MWM) and the novel object recognition (NOR) task. This study employed immunohistochemistry, ELISA, and Western blot to analyze Aβ plaques and proinflammatory factors, investigating neurodegeneration. In contrast, the expression of genes related to neurodegeneration and apoptosis was evaluated using polymerase chain reaction (PCR). Administration of Kenpaullone yielded significant improvements in cognitive performance in the 5XFAD mice. Mice that received the 5 mg/kg treatment demonstrated the highest improvement in spatial learning and recognition memory. Furthermore, Kenpaullone decreased the burden of amyloid-beta plaques in key brain regions associated with memory (hippocampus and cortex), along with decreased levels of proinflammatory cytokines. Furthermore, Kenpaullone treatment resulted in a downregulation of genes related to neurodegeneration and apoptosis, suggesting a potential therapeutic benefit in mitigating neural apoptosis in AD. Our results suggest that Kenpaullone holds promise for improving cognitive function and mitigating neuropathological changes in AD, warranting further exploration as a potential medicinal substance.},
}

@article {pmid40566800,
year = {2025},
author = {Germann, J and Amaral, RSC and Tomaszczyk, J and Yamamoto, K and Elias, GJB and Gouveia, FV and Vasilevskaya, A and Taghdiri, F and Devenyi, GA and Sankar, T and Leoutsakos, JM and Munro, CA and Rosenberg, PB and Lyketsos, CG and Oh, ES and Anderson, WS and Mari, Z and Fosdick, L and Drake, KE and Targum, SD and Pendergrass, JC and Burke, A and Salloway, S and Asaad, WF and Ponce, FA and Sabbagh, M and Wolk, DA and Baltuch, G and Okun, MS and Foote, KD and Giacobbe, P and McAndrews, MP and Tang-Wai, DF and Smith, GS and Tartaglia, MC and Chakravarty, MM and Lozano, AM and , },
title = {Biomarker changes associated with fornix deep brain stimulation in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70394},
doi = {10.1002/alz.70394},
pmid = {40566800},
issn = {1552-5279},
support = {R01AG042165//NIH)/ ; P30 AG066507/AG/NIA NIH HHS/United States ; 202109BPF-471913-BPF-ADHD-184776//Canadian Institutes of Health Research Banting fellowship/ ; R01 NS131342/NS/NINDS NIH HHS/United States ; R01 NR014852/NR/NINR NIH HHS/United States ; R01NS096008//Dr. Okun's research/ ; UH3NS119844//Dr. Okun's research/ ; U01NS119562//Dr. Okun's research/ ; R25NS108939//Dr. Okun is a multi-PI of the NIH/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/pathology/cerebrospinal fluid ; *Deep Brain Stimulation/methods ; *Fornix, Brain/diagnostic imaging ; Male ; Female ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Aged ; *Hippocampus/pathology/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; tau Proteins/cerebrospinal fluid ; Atrophy ; Middle Aged ; },
abstract = {INTRODUCTION: Deep brain stimulation of the fornix (fx-DBS) is being investigated for treatment of Alzheimer's disease (AD). The therapy aims at alleviating memory and cognitive circuit dysfunction. In preclinical models of AD, electrical stimulation of the memory circuit has demonstrated a possible disease-modifying potential. Here we examined changes resulting from fx-DBS in hippocampal atrophy and amyloid accumulation in AD patients with fx-DBS.

METHODS: Repeated magnetic resonance imaging and positron emission tomography (PET) images acquired over the course of 12 months were used to assess changes in hippocampal volume in 36 ADvance trial patients compared to 40 matched untreated AD patients from the Alzheimer's Disease Neuroimaging Initiative, and in 10 separate patients with repeated flutemetamol PET and cerebrospinal fluid (CSF) markers.

RESULTS: We observed a reduction of hippocampal atrophy and amyloid beta (Aβ) PET binding, and an increase in the CSF Aβ/total-tau ratio in DBS patients.

DISCUSSION: These findings highlight the potential of fornix deep brain stimulation to modify AD biomarkers and possibly progression in some patients.

HIGHLIGHTS: Fornix deep brain stimulation (fx-DBS) is being investigated to treat Alzheimer's disease (AD). Results show that fx-DBS modifies imaging and cerebrospinal fluid (CSF) markers. It reduces hippocampal atrophy and increases the amyloid beta/total-tau CSF ratio. These findings highlight the potential of fx-DBS to modify AD.},
}

Humans
*Alzheimer Disease/therapy/diagnostic imaging/pathology/cerebrospinal fluid
*Deep Brain Stimulation/methods
*Fornix, Brain/diagnostic imaging
Male
Female
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Aged
*Hippocampus/pathology/diagnostic imaging
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
tau Proteins/cerebrospinal fluid
Atrophy
Middle Aged

@article {pmid40566684,
year = {2025},
author = {Ban, Y and Jiang, J and Yang, H and Jia, H and Pang, Y and Cheng, X and Yan, J and Liao, Q and Li, C and Lv, B and Feng, Y},
title = {The complete synthetic pathway of echinacoside from Cistanche deserticola and its de novo biosynthesis in yeast.},
journal = {Plant communications},
volume = {},
number = {},
pages = {101430},
doi = {10.1016/j.xplc.2025.101430},
pmid = {40566684},
issn = {2590-3462},
abstract = {Echinacoside (ECH), a representative phenylethanol glycoside, possesses diverse pharmacological properties and has been employed in the treatment of neurodegenerative disorders (e.g., Parkinson's and Alzheimer's diseases), ischemic brain injury, and cancer. The growing therapeutic demand for ECH has highlighted the need for scalable production. However, conventional methods face significant challenges: chemical synthesis is hindered by the compound's structural complexity, while plant extraction is limited by the low natural yield of ECH from Cistanche deserticola, a parasitic desert plant with host-dependent growth. To establish a sustainable microbial biosynthesis platform, we first deciphered the biosynthetic pathway of ECH in C. deserticola by integrating metabolomic analyses of plant tissues and callus cultures. This enabled the identification of key precursors, enzymatic steps, and regulatory mechanisms. Leveraging this knowledge, we engineered Saccharomyces cerevisiae for de novo ECH production by reconstructing the heterologous pathway, achieving a titer of 7.52 ± 1.42 mg/L. Our study not only provides a foundation for the industrial-scale production of ECH but also deepens the understanding of bioactive compound biosynthesis in parasitic plants, offering insights for future pathway engineering efforts.},
}

@article {pmid40566048,
year = {2025},
author = {Țieranu, EN and Cureraru, SI and Târtea, GC and Vladuțu, VC and Cojocaru, PA and Piorescu, MTL and Țieranu, LM},
title = {Acute Myocardial Infarction and Diffuse Coronary Artery Disease in a Patient with Multiple Sclerosis: A Case Report and Literature Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/jcm14124304},
pmid = {40566048},
issn = {2077-0383},
abstract = {Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease that leads to disabilities such as difficulty moving and slowed cognitive processing. It is the leading non-traumatic cause of disability worldwide. MS also has a high potential to become a model for neurodegenerative diseases with a progression like Alzheimer's or Parkinson's. Cardiovascular diseases (CVDs) remain the leading cause of global deaths and have a considerable economic impact. The higher incidence of cardiovascular comorbidities in patients with MS compared to healthy individuals of the same age worsens the prognosis of neurological pathology, leading to a higher level of disability, poorer physical outcomes, higher depression scores, cognitive aging, and diminished quality of life. Classical observational studies often have questionable elements that can represent a source of error, making it difficult to establish a causal relationship between MS and CVD. Genetic studies, including genome-wide evaluation, may resolve this issue and may represent a topic for future research. We report the case of a 31-year-old male patient with a history of multiple sclerosis (MS) diagnosed seven years prior, who presented with acute chest pain upon returning from vacation. Despite the previous recommendation for disease-modifying therapy, the patient had discontinued treatment by personal choice. Electrocardiography (ECG) revealed ST-segment elevation in inferior leads, and emergent coronary angiography identified severe multi-vessel coronary artery disease (CAD), requiring immediate revascularization. This case highlights the potential cardiovascular risks in young patients with MS and the importance of continuous medical supervision.},
}

@article {pmid40566003,
year = {2025},
author = {Theodorou, A and Fanouraki, S and Bakola, E and Papagiannopoulou, G and Palaiodimou, L and Chondrogianni, M and Stefanou, MI and Stavrinou, L and Athanasaki, A and Psychogios, K and Kargiotis, O and Safouris, A and Velonakis, G and Paraskevas, GP and Tsivgoulis, G},
title = {Clinical Management of Cerebral Amyloid Angiopathy.},
journal = {Journal of clinical medicine},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/jcm14124259},
pmid = {40566003},
issn = {2077-0383},
abstract = {Background: Cerebral amyloid angiopathy (CAA) represents a progressive cerebrovascular disorder, characterized by aberrant accumulation of beta-amyloid isoforms in cortical and leptomeningeal vessel walls of cerebrum and cerebellum. Methods: We sought to investigate the clinical manifestations, current different diagnostic tools, various therapeutic strategies and most uncommon subtypes of the disease. Results: The vast majority of CAA remains sporadic, with increasing prevalence with age and very frequent coexistence with Alzheimer's disease. Clinically, CAA can present with spontaneous lobar intracerebral hemorrhage, transient focal neurologic episodes attributed to convexity subarachnoid hemorrhage or cortical superficial siderosis, and progressive cognitive decline leading to dementia. Inflammatory CAA subtype should be recognized early and treated promptly so that better functional outcomes may be achieved. Moreover, genetic and iatrogenic CAA forms are rare, yet increasingly recognized during the last years. Therapeutic management remains challenging for clinicians, especially when markers indicative of higher bleeding risk are present. A targeted therapy does not currently exist. However, various clinical trials are in progress, focusing on offering new promising insights into the disease treatment. Conclusions: This review aims to deepen our understanding of CAA diagnosis and therapeutic approach but also summarizes current evidence on the most uncommon subtypes of this cerebral small-vessel disease.},
}

@article {pmid40565291,
year = {2025},
author = {Uceda, S and Reiriz, M and Echeverry-Alzate, V and Beltrán-Velasco, AI},
title = {The Interplay Between Exosomes and Gut Microbiota in Neuroinflammation: A New Frontier in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125828},
pmid = {40565291},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/pathology/etiology ; *Exosomes/metabolism ; *Gastrointestinal Microbiome ; Animals ; *Neuroinflammatory Diseases/metabolism/microbiology ; Dysbiosis ; Biomarkers/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition that is characterized by the accumulation of amyloid-β, the hyperphosphorylation of tau, and persistent neuroinflammation. However, these hallmarks alone do not fully capture the intricacies of AD pathology, thus necessitating the investigation of emerging mechanisms and innovative tools. Exosomes (nanoscale vesicles involved in cell communication and immune modulation) have emerged as pivotal cellular vehicles due to their dual role-both in the propagation of pathological proteins and the regulation of inflammatory responses. Furthermore, these vesicles have been demonstrated to play a crucial role in the mediation of the effects of microbiota-derived metabolites and the reflection of systemic influences such as dysbiosis, thereby establishing a link between the gut-brain axis and the progression of AD. A comprehensive narrative literature review was conducted using the following databases: ScienceDirect, Scopus, Wiley, Web of Science, Medline, and PubMed, covering studies published between 2015 and 2025. Inclusion and exclusion criteria were established to select research addressing exosomal biogenesis, their functional and diagnosis role, their therapeutic potential, and the emerging evidence on microbiota-exosome interplay in Alzheimer's disease. Exosomes have been identified as integral mediators of intercellular communication, reflecting the molecular state of the central nervous system. These particles have been shown to promote the propagation of pathological proteins, modulate neuroinflammatory responses, and serve as non-invasive biomarkers due to their detectability in peripheral fluids. Advances in exosomal engineering and microbiome-based interventions underscore the potential for targeting systemic and CNS-specific mechanisms to develop integrative therapies for AD. Exosomes present a promising approach for the early diagnosis and personalized treatment of Alzheimer's disease. However, methodological challenges and ongoing controversies, including those related to the influence of systemic factors such as dysbiosis, necessitate multidisciplinary research to optimize and standardize these strategies.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/pathology/etiology
*Exosomes/metabolism
*Gastrointestinal Microbiome
Animals
*Neuroinflammatory Diseases/metabolism/microbiology
Dysbiosis
Biomarkers/metabolism

@article {pmid40565140,
year = {2025},
author = {Zohar, K and Lezmi, E and Reichert, F and Eliyahu, T and Rotshenker, S and Weinstock, M and Linial, M},
title = {Temporal Shifts in MicroRNAs Signify the Inflammatory State of Primary Murine Microglial Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {12},
pages = {},
doi = {10.3390/ijms26125677},
pmid = {40565140},
issn = {1422-0067},
mesh = {Animals ; *MicroRNAs/genetics/metabolism ; *Microglia/metabolism/drug effects/pathology ; Mice ; *Inflammation/genetics/metabolism/pathology ; Lipopolysaccharides/pharmacology ; Cells, Cultured ; Gene Expression Regulation/drug effects ; Signal Transduction/drug effects ; },
abstract = {The primary function of microglia is to maintain brain homeostasis. In neurodegenerative diseases like Alzheimer's, microglia contribute to neurotoxicity and inflammation. In this study, we exposed neonatal murine primary microglial cultures to stimuli mimicking pathogens, injury, or toxins. Treatment with benzoyl ATP (bzATP) and lipopolysaccharide (LPS) triggered a coordinated increase in interleukin and chemokine expression. We analyzed statistically significant differentially expressed microRNAs (DEMs) at 3 and 8 h post-activation, identifying 33 and 57 DEMs, respectively. Notably, miR-155, miR-132, miR-3473e, miR-222, and miR-146b showed strong temporal regulation, while miR-3963 was sharply downregulated by bzATP. These DEMs regulate inflammatory pathways, including TNFα and NFκB signaling. We also examined the effect of ladostigil, a neuroprotective agent known to reduce oxidative stress and inflammation. At 8 h post-activation, ladostigil induced upregulation of anti-inflammatory miRNAs, such as miR-27a, miR-27b, and miR-23b. Our findings suggest that miRNA profiles reflect microglial responses to inflammatory cues and that ladostigil modulates these responses. This model of controlled microglial activation offers a powerful tool with which to study inflammation in the aging brain and the progression of neurodegenerative diseases.},
}

Animals
*MicroRNAs/genetics/metabolism
*Microglia/metabolism/drug effects/pathology
Mice
*Inflammation/genetics/metabolism/pathology
Lipopolysaccharides/pharmacology
Cells, Cultured
Gene Expression Regulation/drug effects
Signal Transduction/drug effects

@article {pmid40564837,
year = {2025},
author = {Alhassan, AM and Altmami, NI},
title = {Fuzzy Optimized Attention Network with Multi-Instance Deep Learning (FOAN-MIDL) for Alzheimer's Disease Diagnosis with Structural Magnetic Resonance Imaging (sMRI).},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/diagnostics15121516},
pmid = {40564837},
issn = {2075-4418},
abstract = {Background/Objectives: Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive neurodegeneration, resulting in cognitive impairment and structural brain changes. Although no curative treatment exists, pharmacological therapies like cholinesterase inhibitors and NMDA receptor antagonists may deliver symptomatic relief and modestly delay disease progression. Structural magnetic resonance imaging (sMRI) is a commonly utilized modality for the diagnosis of brain neurological diseases and may indicate abnormalities. However, improving the recognition of discriminative characteristics is the primary difficulty in diagnosis utilizing sMRI. Methods: To tackle this problem, the Fuzzy Optimized Attention Network with Multi-Instance Deep Learning (FOA-MIDL) system is presented for the prodromal phase of mild cognitive impairment (MCI) and the initial detection of AD. Results: An attention technique to estimate the weight of every case is presented: the fuzzy salp swarm algorithm (FSSA). The swarming actions of salps in oceans serve as the inspiration for the FSSA. When moving, the nutrient gradients influence the movement of leading salps during global search exploration, while the followers fully explore their local environment to adjust the classifiers' parameters. To balance the relative contributions of every patch and produce a global distinct weighted image for the entire brain framework, the attention multi-instance learning (MIL) pooling procedure is developed. Attention-aware global classifiers are presented to improve the understanding of the integral characteristics and form judgments for AD-related categorization. The Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker, and Lifestyle Flagship Study on Ageing (AIBL) provided the two datasets (ADNI and AIBL) utilized in this work. Conclusions: Compared to many cutting-edge techniques, the findings demonstrate that the FOA-MIDL system may determine discriminative pathological areas and offer improved classification efficacy in terms of sensitivity (SEN), specificity (SPE), and accuracy.},
}

@article {pmid40564769,
year = {2025},
author = {Abbas, S and Yeniad, M and Rahebi, J},
title = {Alzheimer's Disease Prediction Using Fisher Mantis Optimization and Hybrid Deep Learning Models.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/diagnostics15121449},
pmid = {40564769},
issn = {2075-4418},
abstract = {Background/Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing memory, cognitive, and behavioral decline. Early and accurate diagnosis is critical for timely treatment and management. This study proposes a novel hybrid deep learning framework, GLCM + VGG16 + FMO + CNN-LSTM, to improve AD diagnosis using MRI data. Methods: MRI images were preprocessed through normalization and noise reduction. Feature extraction combined texture features from the Gray-Level Co-occurrence Matrix (GLCM) and spatial features extracted from a pretrained VGG-16 network. Fisher Mantis Optimization (FMO) was employed for optimal feature selection. The selected features were classified using a CNN-LSTM model, capturing both spatial and temporal patterns. The MLP-LSTM model was included only for benchmarking purposes. The framework was evaluated on The ADNI and MIRIAD datasets. Results: The proposed method achieved 98.63% accuracy, 98.69% sensitivity, 98.66% precision, and 98.67% F1-score, outperforming CNN + SVM and 3D-CNN + BiLSTM by 2.4-3.5%. Comparative analysis confirmed FMO's superiority over other metaheuristics, such as PSO, ACO, GWO, and BFO. Sensitivity analysis demonstrated robustness to hyperparameter changes. Conclusions: The results confirm the efficacy and stability of the GLCM + VGG16 + FMO + CNN-LSTM model for accurate and early AD diagnosis, supporting its potential clinical application.},
}

@article {pmid40564185,
year = {2025},
author = {Madhusudhana, R and Boyle, E and Cen, Y},
title = {An Overview of Glutaminyl Cyclase as a Promising Drug Target for Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061467},
pmid = {40564185},
issn = {2227-9059},
support = {5R01GM143176-04/NH/NIH HHS/United States ; 5UM1TR004360-02/NH/NIH HHS/United States ; 241015//CCTR Endowment Fund of Virginia Commonwealth University/ ; },
abstract = {Alzheimer's disease (AD) has become an increasingly pressing concern for the aging population. Current AD treatments mainly focus on cognitive and neuropsychiatric symptoms-with few FDA-approved treatments targeting disease progression itself. The amyloid cascade hypothesis describes the formation and accumulation of β-amyloid (Aβ) oligomers and plaques as a primary event in AD pathogenesis. This hypothesis has served as the foundation of disease-modifying treatment development over the last decade. Recently, glutaminyl cyclase (QC) has been identified as a potential drug target in the amyloid cascade. QC catalyzes the cyclization of Aβ to form pyroglutamated Aβ (pEAβ). pEAβ acts as the seed for the formation of Aβ plaques, thus preventing the formation of pEAβ via QC inhibition, and offers a promising therapeutic strategy against AD. Here, we offer an overview of the pathway QCI research has followed-from the initial testing of imidazole-based inhibitor scaffolds to QCI structural optimization via pharmacophore identification, Varoglutamstat entering clinical trials, and further avenues of bettering specificity and potency for future QCI development.},
}

@article {pmid40564183,
year = {2025},
author = {Boyuklieva, R and Zahariev, N and Simeonov, P and Penkov, D and Katsarov, P},
title = {Next-Generation Drug Delivery for Neurotherapeutics: The Promise of Stimuli-Triggered Nanocarriers.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061464},
pmid = {40564183},
issn = {2227-9059},
support = {BG-RRP-2.004-0007-C01//European Union-NextGenerationEU, National Recovery and Resilience Plan of the Republic of Bulgaria/ ; },
abstract = {Nanotherapeutics have emerged as novel unparalleled drug delivery systems (DDSs) for the treatment of neurodegenerative disorders. By applying different technological approaches, nanoparticles can be engineered to possess different functionalities. In recent years, the developed, stimuli-responsive nanocarriers stand out as novel complex DDSs ensuring selective and specific drug delivery in response to different endogenous and exogenous stimuli. Due to the multifaceted pathophysiology of the nervous system, a major challenge in modern neuropharmacology is the development of effective therapies ensuring high efficacy and low toxicity. Functionalization of the nanocarriers to react to specific microenvironmental changes in the nervous system tissues or external stimulations significantly enhances the efficacy of drug delivery. This review discusses the microenvironmental characteristics of some common neurological diseases in-depth and provides a comprehensive overview on the progress of the development of exogenous and endogenous stimuli-sensitive nanocarriers for the treatment of Alzheimer's and Parkinson's disease.},
}

@article {pmid40564077,
year = {2025},
author = {Theis, BF and Park, JS and Kim, JSA and Zeydabadinejad, S and Vijay-Kumar, M and Yeoh, BS and Saha, P},
title = {Gut Feelings: How Microbes, Diet, and Host Immunity Shape Disease.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/biomedicines13061357},
pmid = {40564077},
issn = {2227-9059},
abstract = {The human gut microbiome is intricately linked to systemic and organ-specific immune responses and is highly responsive to dietary modulation. As metagenomic techniques enable in-depth study of an ever-growing number of gut microbial species, it has become increasingly feasible to decipher the specific functions of the gut microbiome and how they may be modulated by diet. Diet exerts both supportive and selective pressures on the gut microbiome by regulating a multitude of factors, including energy density, macronutrient and micronutrient content, and circadian rhythm. The microbiome, in turn, contributes to local and systemic immune responses by providing colonization resistance against pathogens, shaping immune cell activity and differentiation, and facilitating the production of bioactive metabolites. Emerging research has strengthened the connections between the gut microbiome and cardiometabolic disorders (e.g., cardiovascular disease, obesity, type-2 diabetes), autoimmune conditions (e.g., type-1 diabetes, rheumatoid arthritis, celiac disease), respiratory disease, chronic kidney and liver disease, inflammatory bowel disease, and neurological disorders (e.g., Alzheimer's, Parkinson's disease, depressive disorders). Here, we outline ways in which dietary factors impact host response in diseases through alterations of gut microbiome functionality and composition. Consideration of diet-mediated microbial effects within the context of the diseases discussed highlights the potential of microbiome-targeted treatment strategies as alternative or adjunct therapies to improve patient outcomes.},
}

@article {pmid40563752,
year = {2025},
author = {Vasileiou, D and Moraitou, D and Diamantaras, K and Papaliagkas, V and Pezirkianidis, C and Tsolaki, M},
title = {Positive Psychology Interventions in Early-Stage Cognitive Decline Related to Dementia: A Systematic Review of Cognitive and Brain Functioning Outcomes of Mindfulness Interventions.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060580},
pmid = {40563752},
issn = {2076-3425},
support = {68/2025//Magda Tsolaki through Association of Alzheimer's Disease and Related Disorders through a scholarship/ ; },
abstract = {Background: Dementia is a global condition affecting over 55 million people. Since there is no treatment, non-pharmacological interventions aim to delay its progression in a safe and cost-effective way. The extant literature suggests that Positive Psychology Interventions (PPIs) can probably be effective for this purpose. The systematic review aims to assess the effectiveness of PPIs as non-pharmacological interventions for mild cognitive decline related to dementia by evaluating their effectiveness in cognitive functions and brain functioning in people with Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and mild Alzheimer's disease dementia (AD). Methods: A comprehensive search conducted in the databases Scopus, PubMed, ScienceDirect and PsychINFO (December 2024-March 2025) published between 2015 and 2025 to identify records that met inclusion criteria: studies included patients with SCD, MCI and mild AD dementia, implemented PPIs, Randomized controlled trials (RCTs) and pre-post intervention studies with measurable outcomes, assess at least one of the following: cognitive functions and brain functioning. Results: The systematic review included 12 studies (N = 669 participants) that can answer the research question. Only mindfulness interventions were identified. Findings suggest that different types of mindfulness interventions, such as the Mindfulness Awareness Program (MAP) and Mindfulness Training (MT), may be efficient for improving specific cognitive functions (e.g., working memory and attention) and influencing biological pathways related to cognitive decline. However, long-term efficacy has not been demonstrated, and results are mixed and unclear. Conclusions: Μindfulness interventions seem promising for enhancing cognition and brain functioning in older adults with cognitive decline, although the data is limited. However, limitations such as the heterogeneity of the studies and the diversity of the interventions make it necessary for more systematic and organized research to be conducted on the implementation of such interventions. At the same time, it is proposed to examine the effectiveness of other constructs of positive psychology, such as character strengths (CS).},
}

@article {pmid40563742,
year = {2025},
author = {Lewandowska, J and Majewski, J and Roszek, K},
title = {Extracellular Vesicles and Purinergic Signaling in Alzheimer's Disease-Joining Forces for Novel Therapeutic Approach.},
journal = {Brain sciences},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/brainsci15060570},
pmid = {40563742},
issn = {2076-3425},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), are a global problem affecting millions of people. Thanks to years of research and huge efforts, it has been possible to discover the pathophysiological changes accompanying Alzheimer's disease at the cellular level. It turns out that the formation of amyloid-beta plaques and hyperphosphorylation of tau protein in the brain play a key role in disease development. Purinergic signaling (PS) is implicated in the pathophysiology of several disorders in the central nervous system, and recent findings link some disturbances in PS with Alzheimer's disease. The primary objective of our review is to comprehensively explore and identify key purinergic signaling targets that hold therapeutic potential in the treatment of patients suffering from the disease. In particular, we focus on the dual role of purinergic compounds and extracellular vesicles (EVs), which have emerged as critical components in cellular communication and disease modulation. The extracellular vesicles that are naturally released by various cells fulfill the role of communication tools, also by harnessing the purinergic compounds. In this context, our review presents a thorough and integrative analysis of how extracellular vesicles can influence purinergic signaling and how this interaction might be leveraged to develop novel, targeted treatment strategies. Ultimately, this line of research may lead to innovative therapeutic approaches that are not only effective in slowing or halting disease progression but also demonstrate a high degree of biocompatibility and safety for the human organism.},
}

@article {pmid40563465,
year = {2025},
author = {Raspudić, A and Odak, I and Mlakić, M and Jelčić, A and Bulava, K and Karadža, K and Milašinović, V and Šagud, I and Pongrac, P and Štefok, D and Barić, D and Škorić, I},
title = {Heterostilbene Carbamates with Selective and Remarkable Butyrylcholinesterase Inhibition: Computational Study and Physico-Chemical Properties.},
journal = {Biomolecules},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/biom15060825},
pmid = {40563465},
issn = {2218-273X},
mesh = {*Butyrylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Humans ; Molecular Docking Simulation ; *Carbamates/chemistry/pharmacology/chemical synthesis ; *Stilbenes/chemistry/pharmacology/chemical synthesis ; Molecular Dynamics Simulation ; Acetylcholinesterase/metabolism/chemistry ; },
abstract = {This manuscript reports the synthesis and characterization of 19 novel heterostilbene carbamates, designed as selective butyrylcholinesterase (BChE) inhibitors with potential applications in the treatment of neurodegenerative disorders, particularly Alzheimer's disease. The compounds were synthesized from resveratrol analogs, and their structures were confirmed by NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction for selected derivatives (compounds 1 and 4). In vitro assays demonstrated high selectivity toward BChE over acetylcholinesterase (AChE), with compound 16 exhibiting exceptional inhibitory activity (IC50 = 26.5 nM). Furthermore, compound 16 showed moderate anti-inflammatory effects by inhibiting LPS-stimulated TNF-α production in peripheral blood mononuclear cells. In silico ADME(T) profiling revealed favorable pharmacokinetic properties and low mutagenic potential for the majority of compounds. Molecular docking and molecular dynamics simulations confirmed stable binding interactions within the BChE active site. These results highlight heterostilbene carbamates as promising lead structures for developing novel therapeutic agents targeting neurodegenerative diseases.},
}

*Butyrylcholinesterase/metabolism/chemistry
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
Humans
Molecular Docking Simulation
*Carbamates/chemistry/pharmacology/chemical synthesis
*Stilbenes/chemistry/pharmacology/chemical synthesis
Molecular Dynamics Simulation
Acetylcholinesterase/metabolism/chemistry

@article {pmid40563347,
year = {2025},
author = {Zhu, X and Chen, X and Wang, M and Hu, H},
title = {Astaxanthin: A Compound in the Prevention of Chronic Diseases and as a Potential Adjuvant Treatment Agent.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/antiox14060715},
pmid = {40563347},
issn = {2076-3921},
abstract = {Astaxanthin (AST) is a fat-soluble carotenoid antioxidant. AST exhibits multiple protective mechanisms, including its antioxidant, anti-inflammatory, immunomodulatory, anti-apoptotic, nervous system-protective, anti-tumor, and anti-fibrotic effects. These effects make it a promising compound for the prevention of chronic diseases. AST can protect the nervous system against neurodegenerative diseases such as Alzheimer's and Parkinson's disease. It also protects the liver and helps reduce the risk of chronic kidney disease. Additionally, it improves cardiovascular health and has anti-diabetic properties. This review aims to provide an updated overview covering the protective effects of AST against various chronic diseases, including its antioxidant, anti-inflammatory, and anti-apoptotic effects. We also discuss the strategies used for improving astaxanthin bioavailability and its potential as an adjuvant therapeutic agent.},
}

@article {pmid40563328,
year = {2025},
author = {Chong, ZZ and Souayah, N},
title = {Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/antiox14060696},
pmid = {40563328},
issn = {2076-3921},
abstract = {Oxidative stress has become a common impetus of various diseases, including neurodegenerative diseases. This review introduces the generation of reactive oxygen species (ROSs) in the nervous system, the cellular oxidative damage, and the high sensitivity of the brain to ROSs. The literature review focuses on the roles of oxidative stress in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Oxidative stress occurs when excessively produced free radicals are beyond the capability of endogenous antioxidants to scavenge, leading to the oxidation of proteins, lipids, and nucleic acids, stimulating neuroinflammatory responses, causing neuronal dysfunction, senescence, and death. The dysfunctional mitochondria and aberrant activities of metabolic enzymes are the major source of ROSs. The high vulnerability of the nervous system to ROSs underlies the critical roles of oxidative stress in neurodegenerative diseases. Gene mutations and other risk factors promote the generation of ROSs, which have been considered a crucial force causing the main pathological features of AD, PD, HD, and ALS. As a result, antioxidants hold therapeutic potential in these neurodegenerative diseases. The elucidation of the pathogenic mechanisms of oxidative stress will facilitate the development of antioxidants for the treatment of these diseases.},
}

@article {pmid40563297,
year = {2025},
author = {Mukhina, KA and Kechko, OI and Osypov, AA and Petrushanko, IY and Makarov, AA and Mitkevich, VA and Popova, IY},
title = {Short-Term Inhibition of NOX2 Prevents the Development of Aβ-Induced Pathology in Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/antiox14060663},
pmid = {40563297},
issn = {2076-3921},
support = {075-00224-24-03//the State Assignment/ ; 19-74-30007//Russian Science Foundation grant/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by the formation of neurotoxic beta-amyloid (Aβ) oligomers in the central nervous system. One of the earliest pathological effects of Aβ is the induction of oxidative stress in brain tissue, mediated by NADPH oxidase 2 (NOX2). This study aimed to determine whether short-term inhibition of NOX2 could disrupt the pathological cascade and prevent the development of Aβ-induced pathology. We demonstrated that suppressing NOX2 activity by GSK2795039 during the first three days after intracerebral Aβ administration prevented the development of the pathological process in mice. Two weeks after the induction of Aβ pathology, animals treated with GSK2795039 showed no neuropsychiatric-like behavioral changes, which correlated with the absence of chronic oxidative damage in brain tissue. Moreover, GSK2795039 prevented microglial activation and reduced microglia-associated neuroinflammation. These findings indicate that short-term NOX2 inhibition effectively suppresses the development of Aβ-induced pathology, suggesting that NOX2 is a potential target for treatment and prevention of AD pathology.},
}

@article {pmid40562637,
year = {2025},
author = {Onda, K and Chotiyanonta, JS and Cowley, HP and Uchida, Y and Nowrangi, MA and Adams, R and Lyketsos, CG and Zandi, PP and Oishi, K},
title = {Brain morphological characteristics predicting clinical response to selective serotonin reuptake inhibitors or cholinesterase inhibitors: A study of electronic medical records in patients with cognitive disorders.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100105},
doi = {10.1016/j.inpsyc.2025.100105},
pmid = {40562637},
issn = {1741-203X},
abstract = {OBJECTIVES: Current treatments for cognitive and neuropsychiatric symptoms in Alzheimer's disease and related dementias (ADRD), such as cholinesterase inhibitors (CEIs) and selective serotonin reuptake inhibitors (SSRIs), show inconsistent effectiveness, necessitating a personalized therapy approach. We aimed to develop predictive models using MRI-derived brain neuroanatomical features and clinical data to forecast responses to CEIs and SSRIs in ADRD patients.

DESIGN AND SETTING: This was a retrospective observational analysis of electronic health records (EHRs) and MRI data conducted within Johns Hopkins Medical Systems.

PARTICIPANTS: Cohort 1 comprised 179 patients prescribed CEIs or SSRIs for the first time with over a year of follow-up. Cohort 2 included 1244 patients with similar criteria to explore clinical characteristics linked to MRI features affecting treatment benefits.

MEASURES: Medication efficacy was assessed via a Likert scale based on EMR descriptions. We quantified brain volumes across 280 anatomical areas on T1-weighted MRIs and applied an elastic net model after harmonizing volumes with the ComBat model. Predictive model efficacy was evaluated using receiver operating characteristic (ROC) analysis.

RESULTS: Preserved volume in the nucleus basalis of Meynert correlated with better responses to both CEIs and SSRIs. Specific white matter volumes related to CEI benefits, while SSRI efficacy was linked to gray matter in the Nucleus Accumbens and frontal cortex. Area under ROC curve values were 0.82 for CEI and 0.75 for SSRI predictions. Older age and vascular factors were associated with reduced medication benefits.

CONCLUSIONS: MRI-derived neuroanatomical features effectively predict medication responses in ADRD, potentially enabling more tailored treatment strategies.},
}

@article {pmid40562636,
year = {2025},
author = {Cummings, JL and Zhong, K and Ballard, C and Sano, M and Mintzer, J},
title = {Clinical trials for neuropsychiatric syndromes in major and mild neurocognitive disorders: A CONSORT-based approach.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100107},
doi = {10.1016/j.inpsyc.2025.100107},
pmid = {40562636},
issn = {1741-203X},
abstract = {Neuropsychiatric syndromes (NPS) such as agitation, psychosis, apathy, and irritability are among the most disabling features of major and mild neurocognitive disorders including Alzheimer's disease, other neurodegenerative disorders (NDD), and vascular cognitive impairment. Clinical trial methodologies for the treatment of these syndromes are evolving and the first agents to reduce NPS severity has been approved. Biomarkers are rapidly becoming available to guide clinical trial decision-making. Biomarkers can confirm the diagnosis of Alzheimer's disease and are playing a larger role in non-Alzheimer trials. The Consolidated Standards for Reporting Trials (CONSORT) specify the elements of clinical trials that must be reported when clinical trials are published. These criteria provide conventions for uniform reporting of all key aspects of a clinical trial and facilitate comparisons across trials. We describe best practices for clinical trials of NPS including research definitions of the NDD, use of biomarkers to support clinical diagnosis, research criteria for NPS, use of rating scales to define the severity of NPS at baseline and as endpoints for the clinical trial, and approaches to data analysis of specific interest in NPS trials. Standards for describing the limitations of trials and their generalizability are provided. The goal is to inform planning and reporting of NPS trials including the use of biomarkers based on CONSORT guidelines for best trial practices.},
}

@article {pmid40562341,
year = {2025},
author = {Hung, WC and Sun, WC and Su, TC and Lee, YJ and Cheng, IH},
title = {FGFR1 agonists alleviate pathology and cognitive impairment in an Alzheimer's disease mouse model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115357},
doi = {10.1016/j.expneurol.2025.115357},
pmid = {40562341},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by the buildup of amyloid plaques and neurofibrillary tangles, which lead to neuronal damage and trigger inflammatory responses in glial cells. The fibroblast growth factor receptor 1 (FGFR1)-mediated signaling pathways support the function of damaged neurons and modulate the inflammatory response. The FGFR1 agonists, including Fibroblast growth factor 1 (FGF1) and FG loop peptide (FGL), have been implicated in multiple disease therapies. However, whether FGFR1 agonists can improve pathology and cognitive function in AD remains unknown. This study showed that administration of FGF1 and FGL to the AD mouse model reversed spatial memory impairment, enhanced neurogenesis, suppressed reactive astrogliosis, and restricted dystrophic neurites. However, only FGF1 treatment reduced the deposition of senile plaque. In microglial culture studies, FGF1 improves the phagocytosis ability of microglia, but this effect is blocked by the FGFR1-specific inhibitor. Together, our findings suggested that FGFR1 agonists alleviate pathological and cognitive impairments in the AD mouse model.},
}

@article {pmid40560947,
year = {2025},
author = {Krick, KE and Wilcock, DM},
title = {A Change of Mind: Targeting Amyloid-β with Better Safety Profile.},
journal = {Annual review of pharmacology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-pharmtox-062124-113434},
pmid = {40560947},
issn = {1545-4304},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease that leads to cognitive decline and dementia. Over the past two decades, many scientists have contributed to the discovery of therapeutics that target amyloid-beta (Aβ) to slow the progression of AD. These discoveries have led to the development of the first disease-modifying therapeutics in AD, though these come with the risk of side effects known as amyloid-related imaging abnormalities (ARIA). There are currently many exciting studies and trials working to mitigate ARIA risk that range from modifying antibodies to potential combination therapeutics. This review addresses some of the ongoing research areas for improving safety in Aβ targeting as well as clinical considerations for current patient treatment.},
}

@article {pmid40560244,
year = {2025},
author = {Alum, EU and Akwari, AA and Okoroh, PN and Aniokete, UC and Abba, JN and Uti, DE},
title = {Phytochemicals as modulators of ferroptosis: a novel therapeutic avenue in cancer and neurodegeneration.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {636},
pmid = {40560244},
issn = {1573-4978},
mesh = {*Ferroptosis/drug effects ; Humans ; *Phytochemicals/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neoplasms/drug therapy/metabolism ; Oxidative Stress/drug effects ; Animals ; Lipid Peroxidation/drug effects ; Antioxidants/pharmacology ; Iron/metabolism ; Catechin/analogs & derivatives ; },
abstract = {Ferroptosis, a controlled cell death mechanism characterised by iron-dependent lipid peroxidation, has become a significant factor in the pathophysiology of cancer and neurodegenerative disorders. Its dual role as a tumor suppressor and mediator of neuronal damage highlights its significance as a therapeutic target. Phytochemicals, natural bioactive molecules in plants, have attracted interest for their ability to modulate ferroptosis through diverse mechanisms, including regulation of oxidative stress, iron metabolism, and antioxidant defense systems. This review examines the complex relationship between ferroptosis and disease mechanisms, emphasizing its relevance in treatment-resistant cancers and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Information was taken from reputable databases such as PubMed, Scopus, and Web of Science. We thoroughly analyzed the current evidence on phytochemicals-including polyphenols like curcumin and epigallocatechin gallate, flavonoids like quercetin and luteolin, and alkaloids like berberine-as modulators of ferroptotic pathways. Despite their promising therapeutic potential, challenges such as limited bioavailability, pharmacokinetics, and clinical validation remain significant hurdles. Future research focusing on advanced delivery systems, synergistic approaches, and personalized medicine strategies could unlock the full potential of phytochemicals in ferroptosis-targeted therapies. This review underscores phytochemicals as a novel and versatile avenue in addressing the unmet therapeutic needs in cancer and neurodegenerative diseases.},
}

*Ferroptosis/drug effects
Humans
*Phytochemicals/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
*Neoplasms/drug therapy/metabolism
Oxidative Stress/drug effects
Animals
Lipid Peroxidation/drug effects
Antioxidants/pharmacology
Iron/metabolism
Catechin/analogs & derivatives

@article {pmid40559632,
year = {2025},
author = {Zhang, R and Ren, Y and Ren, T and Yu, Y and Li, B and Zhou, X},
title = {Marine-Derived Antioxidants: A Comprehensive Review of Their Therapeutic Potential in Oxidative Stress-Associated Diseases.},
journal = {Marine drugs},
volume = {23},
number = {6},
pages = {},
pmid = {40559632},
issn = {1660-3397},
mesh = {*Oxidative Stress/drug effects ; *Antioxidants/pharmacology/therapeutic use/chemistry/isolation & purification ; Humans ; *Aquatic Organisms/chemistry ; Animals ; Neurodegenerative Diseases/drug therapy ; Cardiovascular Diseases/drug therapy ; *Biological Products/pharmacology ; Reactive Oxygen Species/metabolism ; },
abstract = {Oxidative stress is a critical factor contributing to the pathogenesis of numerous diseases, including cardiovascular disorders, diabetes, and neurodegenerative conditions. In recent years, marine-derived antioxidants have emerged as promising therapeutic agents due to their unique biological activities and diverse sources. This comprehensive review explores the therapeutic potential of various marine antioxidants in mitigating oxidative stress-associated diseases. Marine organisms are rich in bioactive compounds, such as polysaccharides, polyphenols, carotenoids, peptides, and vitamins, which exhibit potent antioxidant and free radical scavenging abilities. These compounds have been shown to effectively inhibit oxidative reactions, repair oxidative damage, and enhance the body's antioxidant defense mechanisms. For instance, marine polysaccharides and their derivatives can scavenge reactive oxygen species (ROS), protect neurons from oxidative damage, and alleviate inflammation in neurodegenerative diseases like Alzheimer's and Parkinson's diseases. Similarly, marine unsaturated fatty acids, such as omega-3 polyunsaturated fatty acids (PUFAs), have been found to reduce cardiovascular risks by lowering serum triglyceride levels and improving vascular endothelial function. Additionally, marine-derived superoxide dismutase (SOD) plays a crucial role in neutralizing ROS, thereby offering protection against oxidative stress in various diseases. Despite these promising findings, challenges remain in the field, including the need for improved extraction and purification technologies, more comprehensive activity evaluation systems, and further research into the safety and bioavailability of these compounds. This review provides a detailed overview of the current research status, highlighting the types, structural characteristics, antioxidant activities, and mechanisms of action of marine antioxidants. It also identifies key areas for future research and development, aiming to harness the full potential of marine-derived antioxidants in the prevention and treatment of oxidative stress-related diseases.},
}

*Oxidative Stress/drug effects
*Antioxidants/pharmacology/therapeutic use/chemistry/isolation & purification
Humans
*Aquatic Organisms/chemistry
Animals
Neurodegenerative Diseases/drug therapy
Cardiovascular Diseases/drug therapy
*Biological Products/pharmacology
Reactive Oxygen Species/metabolism

@article {pmid40568390,
year = {2024},
author = {Wilhelmsen, KC and D'Haese, PF and Haut, MW and Marano, GD and Mehta, RI and Wang, X and Ward, M and Miller, M and Najib, U and Navia, RO and Keith, CM and Rezai, A},
title = {Metabolism as a biomarker for treatment success in anti-amyloid therapy: A case report.},
journal = {Neuroimage. Reports},
volume = {4},
number = {2},
pages = {100203},
pmid = {40568390},
issn = {2666-9560},
abstract = {This case report investigates the potential use of metabolism as a sensitive biomarker in monitoring the effectiveness of anti-amyloid therapy in a patient with mild cognitive impairment due to early Alzheimer's disease. The study centers around a 74-year-old male patient treated with aducanumab, a monoclonal antibody developed for anti-amyloid therapy. Alongside an expected decline in cerebral amyloid monitored using PET amyloid tracers, we observed significant improvements in the patient's brain metabolic activity, measured via 18-fluorodeoxyglucose positron emission tomography (FDG PET). Despite limitations posed by the single-patient case study, the findings invite further research and consider the utilization of FDG PET as a surrogate for clinically meaningful changes in the treatment of early Alzheimer's disease. These findings suggest the potential for more personalized and effective therapeutic interventions.},
}

@article {pmid40568443,
year = {2021},
author = {Clayton, D and Coimbra, A and Faraji, F and Bengtsson, T and Honigberg, L and Cho, W and Paul, R and de Crespigny, A},
title = {Resting-state functional magnetic resonance imaging in a randomized clinical trial for Alzheimer's disease.},
journal = {Neuroimage. Reports},
volume = {1},
number = {4},
pages = {100055},
pmid = {40568443},
issn = {2666-9560},
abstract = {Resting-state functional connectivity has been used to study Alzheimer's disease, revealing underlying differences between groups of individuals at different levels of cognitive impairment, or groupwise changes over time. Most of these studies have employed a single scanner and/or a single scan per subject. In this study, we used data collected from a substudy to two randomized clinical trials in patients with mild-to-moderate Alzheimer's Disease to investigate the robustness of functional connectivity in a multicenter, longitudinal setting. This substudy was not powered to detect drug treatment effects. With a basic imaging charter for inter-site acquisition standardization, we found no changes to functional connectivity over time in the placebo group, despite observable changes in clinical test scores and regional brain atrophy. We infer that functional connectivity, as implemented in our study, is not sensitive enough to detect disease progression in our patients. Using an 8-week interval between scans (in both treatment and placebo groups), we found that our test-retest reproducibility was comparable with other published results. We also found that the dominant source of measurement variability was within individuals over time, compared with variability between subjects and sites. Finally, we propose a simple method of visual inspection to identify scans that should be excluded from longitudinal analysis.},
}

@article {pmid40559320,
year = {2025},
author = {Gharaibeh, S and Alsabbah, A and Alloubani, A and Gharaibeh, A},
title = {Reciprocal Interactions Between Periodontal Disease and Alzheimer's Disease: Implications for Mutual Triggering, Exacerbation, and Treatment Interventions-A Comprehensive Review of the Literature.},
journal = {Neurology international},
volume = {17},
number = {6},
pages = {},
doi = {10.3390/neurolint17060081},
pmid = {40559320},
issn = {2035-8385},
abstract = {Periodontal health is connected to many systemic diseases, such as cardiovascular, diabetes mellitus, and neurodegenerative diseases. The oral-brain axis has gained increasing interest in the pathogenesis of diseases. Emerging studies have highlighted the potential role of periodontal disease in the development and progression of Alzheimer's disease. However, Alzheimer's disease also affects periodontal disease and oral health. In this review, we address the correlation between the two diseases and the mechanisms by which one contributes to the other. Exploring the correlation between Alzheimer's disease and periodontal disease will assist in better understanding the pathophysiology of diseases and pave the way for the development of therapeutic and preventive strategies.},
}

@article {pmid40559212,
year = {2025},
author = {Lee, AW and Hirani, R and Ogulnick, J and Tiwari, RK and Etienne, M},
title = {Emerging Therapies for Neurological Disorders: A Clinical Review of MANAGED (Music, Art, Nature-Based, Animal-Assisted, Game, Essential Oil, Dance) Care.},
journal = {NeuroSci},
volume = {6},
number = {2},
pages = {},
doi = {10.3390/neurosci6020051},
pmid = {40559212},
issn = {2673-4087},
abstract = {In the face of the limitations in pharmacological and surgical interventions for neurological conditions such as Parkinson's and Alzheimer's disease, patients are increasingly turning to non-pharmacological and alternative therapies to manage their symptoms and improve their quality of life. This shift underscores the urgent need for accessible, effective, and affordable treatments. This literature review examines a range of alternative and personalized therapies, including game therapy, animal-assisted therapy, dance therapy, art therapy, music therapy, aroma therapy, and shinrin-yoku therapy. These modalities have demonstrated promising results in mitigating symptoms and enhancing well-being among individuals grappling with neurological disorders. Moreover, these therapies offer a holistic approach that complements traditional medical interventions, underscoring the importance of integrating diverse treatment modalities. Despite their historical roots in non-clinical settings, their potential in modern clinical practice remains untapped. The findings suggest the necessity for further research, particularly large cohort studies, to validate the efficacy of these personalized therapies and advocate for their widespread adoption. In an era marked by escalating healthcare costs, the exploration of alternative therapies presents a compelling avenue for enhancing patient care while simultaneously addressing economic challenges within the healthcare system.},
}

@article {pmid40559126,
year = {2025},
author = {Li, Z and Zhang, Y and Su, R and Yang, J and Chen, F and Chen, L and Yao, C and Li, S and Cui, P and Meng, X and Huang, G},
title = {Notoginsenoside R1, a Novel Natural PPARγ Agonist, Attenuates Cognitive Deficits in a Mouse Model of Diabetic Alzheimer's Disease Through Enhancing GLUT4-Dependent Neuronal Glucose Uptake.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70006},
pmid = {40559126},
issn = {1099-1573},
support = {82474108//National Natural Science Foundation of China/ ; 82371423//National Natural Science Foundation of China/ ; 2023A1515220241//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515030035//Natural Science Foundation of Guangdong Province/ ; 2022A1515012323//Natural Science Foundation of Guangdong Province/ ; 2021A151510836//Natural Science Foundation of Guangdong Province/ ; //Shenzhen Science and Technology Program/ ; JCYJ20220530151006013//Basic research projects of Shenzhen Science and Technology Program/ ; JCYJ20180507184656626//Basic research projects of Shenzhen Science and Technology Program/ ; ZDSYS20140509173142601//Shenzhen Key Laboratory of Neurosurgery/ ; RCBS20210609104629074//Shenzhen Development and Reform Commissions Stroke Screening and Prevention Public Service Platform improving program/ ; //Guangdong Innovation Platform of Translational Research for Cerebrovascular Diseases/ ; },
abstract = {Our previous studies demonstrated the potential of notoginsenoside R1 (NGR1), a primary bioactive compound from Panax notoginseng, in alleviating diabetic encephalopathy in db/db mice and mitigating amyloid-β (Aβ)-induced neuronal damage. This study aimed to investigate the positive effects of NGR1 against cognitive deficits in a diabetic Alzheimer's disease (AD) mouse model (APP/PS1xdb/db mice). APP/PS1xdb/db mice were intragastrically administrated with NGR1 (40 mg/kg/day) or co-administrated with NGR1 and a selective PPARγ inhibitor GW9662 for 16 weeks. We identified NGR1 as a novel PPARγ agonist through molecular docking, surface plasmon resonance, and dual-luciferase reporter assay. NGR1 treatment significantly promoted the membrane translocation of GLUT4 and enhanced 2-deoxyglucose uptake in primary mouse hippocampal neurons. Furthermore, NGR1 treatment notably mitigated cognitive deficits in APP/PS1xdb/db mice. This treatment correlated with reduced blood glucose levels, lowered blood HbA1c, and decreased serum insulin levels, coupled with enhanced glucose tolerance and insulin sensitivity. Additionally, NGR1 treatment ameliorated Aβ burden, suppressed microglia-induced neuroinflammation, and notably increased cerebral glucose uptake, as demonstrated by [18]F-FDG PET scans. NGR1 treatment could upregulate PPARγ and GLUT4 expression and increase phosphorylation of Akt at Ser473 while decreasing phosphorylation of IRS-1 at Ser616 in the hippocampus of APP/PS1xdb/db mice. Crucially, the protective effects of NGR1 were abolished by co-administration with GW9662. NGR1 demonstrated efficacy in enhancing neuronal glucose uptake through the activation of the PPARγ/Akt/GLUT4 signaling pathways in APP/PS1xdb/db mice, positioning it as a promising candidate for diabetic AD treatment.},
}

@article {pmid40558561,
year = {2025},
author = {Jarne-Ferrer, J and Pallàs, M and Griñán-Ferré, C and Bellver-Sanchis, A},
title = {Investigating the Synergistic Neuroprotective Effects of Plant-Derived Antioxidants and the Psychedelic N,N-Dimethyltryptamine in Alzheimer's Disease Therapy.},
journal = {Cells},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/cells14120934},
pmid = {40558561},
issn = {2073-4409},
mesh = {*Alzheimer Disease/drug therapy/pathology ; Animals ; *Antioxidants/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Caenorhabditis elegans/drug effects ; Oxidative Stress/drug effects ; Drug Synergism ; Amyloid beta-Peptides/metabolism ; Humans ; Disease Models, Animal ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a chronic and complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and irreversible impairment of brain functions. The etiology of AD is multifactorial, involving a complex interplay of genetic, environmental, and physiological factors, including the aggregation of amyloid-β (Aβ) and oxidative stress (OS). The role of OS in AD pathogenesis is of particular significance, given that an imbalance between oxidants and antioxidants promotes cellular damage, exacerbates Aβ deposition, and leads to cognitive deterioration. Despite extensive research, current therapeutic strategies have largely failed, likely due to the use of single-target drugs unable to halt the multifactorial progression of the disease. In this study, we investigated the synergistic therapeutic effect of plant-derived bioactive compounds Withanone, Apigenin, Bacoside A, Baicalin, and Thymoquinone in combination with N,N-Dimethyltryptamine (NN-DMT), a psychedelic molecule. We used a transgenic Caenorhabditis elegans model to assess the behavioral and molecular outcomes following compound exposure. Motility assays, thioflavin S staining, and survival assays under oxidative stress were employed to evaluate the treatment efficacy. The results of the behavioral and molecular analyses indicated that the combination therapy exhibited a higher efficacy than the monotherapies, leading to a significant reduction in age-related motility defects in the AD model. Furthermore, the combination treatment substantially reduced Aβ plaque burden, enhanced survival following OS insult, and demonstrated a synergistic effect in mitigating AD-related hallmarks. Taken together, these findings support the potential of combining NN-DMT with specific bioactive compounds as a promising multi-target therapeutic approach for AD.},
}

*Alzheimer Disease/drug therapy/pathology
Animals
*Antioxidants/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
Caenorhabditis elegans/drug effects
Oxidative Stress/drug effects
Drug Synergism
Amyloid beta-Peptides/metabolism
Humans
Disease Models, Animal
Animals, Genetically Modified

@article {pmid40558456,
year = {2025},
author = {Arpaia, P and Cacciapuoti, M and Cataldo, A and Criscuolo, S and De Benedetto, E and Masciullo, A and Pesola, M and Schiavoni, R},
title = {Assessing the Role of EEG Biosignal Preprocessing to Enhance Multiscale Fuzzy Entropy in Alzheimer's Disease Detection.},
journal = {Biosensors},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/bios15060374},
pmid = {40558456},
issn = {2079-6374},
support = {B89J23002490005//Italian Ministry of Enterpise and Made in Italy/ ; B69J23001290005//Italian Ministry of Enterpise and Made in Italy/ ; PNRR DM 351/2022 - M4C1//Italian Ministry of University and Research/ ; },
mesh = {*Alzheimer Disease/diagnosis ; *Electroencephalography/methods ; Humans ; Entropy ; Fuzzy Logic ; Support Vector Machine ; *Signal Processing, Computer-Assisted ; Algorithms ; },
abstract = {Quantitative electroencephalography (QEEG) has emerged as a promising tool for detecting Alzheimer's disease (AD). Among QEEG measures, Multiscale Fuzzy Entropy (MFE) shows great potential in identifying AD-related changes in EEG complexity. However, MFE is intrinsically linked to signal amplitude, which can vary substantially among EEG systems, and this hinders the adoption of this metric for AD detection. To overcome this issue, this study investigates different preprocessing strategies to make the calculation of MFE less dependent on the specific amplitude characteristics of the EEG signals at hand. This contributes to generalizing and making more robust the adoption of MFE for AD detection. To demonstrate the robustness of the proposed preprocessing methods, binary classification tasks with Support Vector Machines (SVMs), Random Forest (RF), and K-Nearest Neighbor (KNN) classifiers are used. Performance metrics, such as classification accuracy and Matthews Correlation Coefficient (MCC), are employed to assess the results. The methodology is validated on two public EEG datasets. Results show that amplitude transformation, particularly normalization, significantly enhances AD detection, achieving mean classification accuracy values exceeding 80% with an uncertainty of 10% across all classifiers. These results highlight the importance of preprocessing in improving the accuracy and the reliability of EEG-based AD diagnostic tools, offering potential advancements in patient management and treatment planning.},
}

*Alzheimer Disease/diagnosis
*Electroencephalography/methods
Humans
Entropy
Fuzzy Logic
Support Vector Machine
*Signal Processing, Computer-Assisted
Algorithms

@article {pmid40558228,
year = {2025},
author = {Niculescu, V and Dimitriu, AL and Nistor-Cseppento, DC and Tirla, S and Gherle, A and Uivaraseanu, B and Burnei, C},
title = {Multicenter Study of Comorbidities in Patients with Periprosthetic Fractures After Total Hip Arthroplasty and Their Association with Immediate Postoperative Complications.},
journal = {Clinics and practice},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/clinpract15060110},
pmid = {40558228},
issn = {2039-7275},
abstract = {Background/Objectives: Periprosthetic fractures (PFs) can occur in both the upper and lower limbs, commonly resulting from falls at the same level. The frequency of PFs following total hip arthroplasty (THA) ranges from 0.045% to 4.1%, and this incidence is influenced by several factors, including age, gender, the type of prosthesis used, and existing comorbidities. Previous studies on this subject have been small in scale and did not adequately address the associated comorbidities, which pose a challenge for the aging population. This study aims to comparatively assess the incidence of THA-related PFs, immediate postoperative complications, and comorbidities in patients with PFs from three emergency hospitals. Methods: A retrospective observational study was conducted from 1 January to 31 December 2024, in which 54 patients with PFs hospitalized in three emergency hospitals (Bucharest, Oradea, and Ploiești) were evaluated, divided into Group B (n = 29), Group O (n = 14), and Group P (n = 11). Results: Of all patients with PFs, 81.48% had minor complications-grade 1, 9.26% had grade 2 complications (complications requiring medical treatment or other minor interventions), and 3.70% had complications requiring surgery or invasive procedures. Clavien-Dindo grade 5 (patient death) had an incidence of 3.70%. Cardiac pathology was the most common pathology; hypertension predominated in Group O (42.85%). Alzheimer's disease was associated in 7 patients (12.96%). Without associated pathology, about 13% of patients were identified. Diabetes mellitus also occurred frequently in 31.50%. Data analysis indicates a very weak positive correlation between the Dindo Index and the Charlson Comorbidity Index (r = 0.046), which is not statistically significant (p = 0.628). The effect size, measured by Fisher's z, is also reported as 0.046. Conclusions: No significant differences were found among the evaluated centers regarding therapeutic approaches, postoperative complications, and associated comorbidities. Furthermore, there is insufficient evidence to suggest a significant association between the Charlson Comorbidity Index and the Clavien-Dindo Index.},
}

@article {pmid40558015,
year = {2025},
author = {Tanaka, T and Suzuki, H and Taruta, H and Saga, A and Li, G and Fujisawa, S and Kaneko, MK and Kato, Y},
title = {Development of a Novel Anti-human EphA1 Monoclonal Antibody, Ea1Mab-30, for Multiple Applications.},
journal = {Monoclonal antibodies in immunodiagnosis and immunotherapy},
volume = {44},
number = {3},
pages = {41-52},
doi = {10.1089/mab.2025.0006},
pmid = {40558015},
issn = {2167-9436},
mesh = {Humans ; Animals ; *Receptor, EphA1/immunology/genetics ; CHO Cells ; Cricetulus ; *Antibodies, Monoclonal/immunology/biosynthesis ; Mice ; Caco-2 Cells ; Cricetinae ; Antibody Specificity/immunology ; Cell Line, Tumor ; },
abstract = {Erythropoietin-producing hepatocellular receptor A1 (EphA1) is one of the Eph receptor family members, the largest group of receptor tyrosine kinases. EphA1 is expressed in various tissues and regulates cellular homeostasis by interacting with its membrane-bound ephrin ligands and other receptors. EphA1 critically correlates with the pathogenesis in several disorders, including Alzheimer's disease and cancers. Therefore, establishing sensitive monoclonal antibodies (mAbs) for EphA1 has been desired for basic research, diagnosis, and treatment. In this study, a novel specific and sensitive anti-human EphA1 mAb, clone Ea1Mab-30 (mouse IgG1, kappa), was established by the Cell-Based Immunization and Screening (CBIS) method. Ea1Mab-30 demonstrated reactivity with an EphA1-overexpressed Chinese hamster ovary-K1 cell line (CHO/EphA1), an endogenously EphA1-expressing bladder carcinoma cell line (5637), and a colorectal adenocarcinoma cell line (Caco-2) in flow cytometry. Crossreactivities of Ea1Mab-30 with other Eph receptors were not observed. Furthermore, the values of apparent binding affinity for CHO/EphA1 and 5637 were determined to be 8.9 × 10[-9] M and 1.7 × 10[-9] M, respectively. Furthermore, Ea1Mab-30 detected EphA1 protein in CHO/EphA1 and 5637 lysates using Western blot analysis. Ea1Mab-30 also clearly stained EphA1 of formalin-fixed paraffin-embedded CHO/EphA1 using immunohistochemistry. Ea1Mab-30, established by CBIS method, could help analyze the EphA1-contributed cellular functions and have potential applications in pathological diagnosis and treatment with specificity and high affinity for EphA1-expressing cells.},
}

Humans
Animals
*Receptor, EphA1/immunology/genetics
CHO Cells
Cricetulus
*Antibodies, Monoclonal/immunology/biosynthesis
Mice
Caco-2 Cells
Cricetinae
Antibody Specificity/immunology
Cell Line, Tumor

@article {pmid40556661,
year = {2025},
author = {Ahammad, RU and Spencer, B and Quach, B and Salehi, S and Rissman, RA},
title = {A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70117},
pmid = {40556661},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders characterized by abnormal protein aggregation, with amyloid beta (Aβ) and α-synuclein (α-syn) as key pathological markers. Increasing evidence highlights a pathological interplay between Aβ and α-syn, exacerbating neurodegeneration in both AD and PD. In this study, we evaluated the effects of reducing amyloid precursor protein (APP) processing on α-syn pathology using a splice-switching oligonucleotide (SSO) targeting APP exon 15 in Thy1-α-syn transgenic (α-syn-tg) mice.

METHODS: α-syn-tg mice received systemic APP SSO treatment. Immunohistochemistry and immunoblotting assessed α-syn, phosphorylated α-syn (P-Syn), and APP C-terminal fragments (CTFs) in the cortex, hippocampus, and thalamus. Neuronal integrity in different brain regions were examined, and behavioral assessments evaluated cognitive and motor functions.

RESULTS: APP SSO treatment significantly reduced α-syn and P-Syn in the cortex, hippocampus, and thalamus while also reversing neuronal loss in the hippocampal CA3 region. Interestingly, α-syn-tg mice exhibited elevated levels of alternative APP CTFs, which were reduced by APP SSO treatment, implicating APP processing dysregulation in α-syn pathology. Although behavioral assessments revealed no significant impairments or improvements in female α-syn-tg mice.

DISCUSSION: Our findings demonstrate that targeting APP reduces α-syn pathology and rescues neuronal loss, supporting the therapeutic potential of APP modulation in synucleinopathies. While no behavioral changes were observed in transgenic mice, further research exploring different models and conditions may provide additional insights into the full range of therapeutic benefits. Future studies should optimize delivery methods and explore combination therapies to enhance outcomes in neurodegenerative diseases with overlapping proteinopathies.

HIGHLIGHTS: APP-targeting SSO reduces α-syn and P-Syn in α-syn-tg mice.APP SSO lowers APP CTFs, linking APP processing to α-syn pathology.Neuronal loss in the hippocampal CA3 region is restored following APP SSO treatment.Behavioral assessments show no significant changes in female α-syn-tg mice.Findings support APP modulation as a potential strategy for synucleinopathies.},
}

@article {pmid40556653,
year = {2025},
author = {Lan, Y and Ding, J and Yu, T and Cheng, C},
title = {Research progress of platelets in neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1544605},
pmid = {40556653},
issn = {1663-4365},
abstract = {Neurodegenerative disease (NDD) is a disease state characterized by the loss of neuronal cells in the brain and spinal cord, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). They have become a major challenge for the world's health system in the twenty-first century, with an increasing incidence year by year, complex and diverse causes, and a lack of effective therapeutic. The brain and spinal cord are composed of neurons, and activated platelets are highly similar to neurons. The occurrence and development of these diseases are often accompanied by platelet activation, suggesting that platelets play an important role in the pathological process of NDDs. This article reviews the research progress of platelets in common NDDs, and elaborates on the mechanisms of platelets' involvement in NDDs and the use as a therapeutic option for NDDs to providing new ideas for the diagnosis and treatment of NDDs.},
}

@article {pmid40556526,
year = {2025},
author = {Yener, K and Hayat, A},
title = {Evaluation of the effects of tideglusib and calcium sulfate on the healing of experimental bone defects in rabbits.},
journal = {Polish journal of veterinary sciences},
volume = {28},
number = {2},
pages = {213-223},
doi = {10.24425/pjvs.2025.154940},
pmid = {40556526},
issn = {2300-2557},
mesh = {Animals ; Rabbits ; *Calcium Sulfate/pharmacology/therapeutic use/administration & dosage ; Bone Regeneration/drug effects ; Bone Transplantation/veterinary ; Wound Healing/drug effects ; Male ; },
abstract = {This study aimed to evaluate the effects of tideglusib and bone graft mixture on bone healing. Tideglusib is a drug used in the treatment of various neurological disorders such as Alzheimer's disease. In a relevant study, the positive effect of tideglusib on the Wnt pathway, one of the pathways involved in bone regeneration and dentin tissue regeneration, was demonstrated. Dentin and bone tissues have structurally similar healing mechanisms. Therefore, tideglusib may have a similar effect on the bone tissue. The main goal of bone grafting is to provide bone regeneration and functional healing through remodeling. Bone graft materials are divided into four types based on their source: autogenous, allogenous, xenogenous, and alloplastic. Because these graft materials have various advantages and disadvantages, research continues to focus on alternative materials and applications. Sixteen New Zealand rabbits were included in this study. A unicortical 3.5 mm diameter defect was created in the tibia of rabbits under general anesthesia. The groups in the study were as follows: Group 1, left proximal tibia defect area was controlled (defect area was left empty); Group 2, left distal tibia defect area was treated with tideglusib + calcium sulfate; Group 3, right proximal tibia defect area was treated with calcium sulfate only; Group 4, right distal tibia defect area was treated with tideglusib only. Mediolateral (M/L) radiographs of the tibia were taken on the 30th and 60th postoperative days. On the 30th day, the first eight rabbits were sacrificed, and on the 60th day, the remaining eight were sacrificed for histopathological examination. New bone formation in the obtained samples was evaluated by radiological and histopathological analyses. The study concluded that the combination of tideglusib and calcium sulfate significantly enhanced bone healing compared with the other groups (p<0.005). This suggests that tideglusib, either alone or in combination with bone graft materials, could serve as a promising alternative for the repair of bone defects.},
}

Animals
Rabbits
*Calcium Sulfate/pharmacology/therapeutic use/administration & dosage
Bone Regeneration/drug effects
Bone Transplantation/veterinary
Wound Healing/drug effects
Male

@article {pmid40556306,
year = {2025},
author = {McVea, A and DiFilippo, A and McLachlan, M and Betcher, B and Zammit, M and Betthauser, TJ and Converse, A and Murali, D and Stone, C and Hartley, S and Johnson, S and Tudorascu, DL and Laymon, CM and Cohen, AD and Minhas, D and Luo, W and Mathis, C and Lao, PJ and Ances, B and Zaman, S and Mapstone, M and Head, E and Handen, BL and Christian, BT and , },
title = {PET-measured amyloid beta accumulates at an accelerated rate in Down syndrome compared to neurotypical populations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70357},
doi = {10.1002/alz.70357},
pmid = {40556306},
issn = {1552-5279},
support = {//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; /AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Down Syndrome/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; *Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism ; Middle Aged ; *Brain/diagnostic imaging/metabolism ; Adult ; Aged ; Aniline Compounds ; Thiazoles ; },
abstract = {INTRODUCTION: Individuals with Down syndrome (DS) have a high prevalence of Alzheimer's disease (AD) and reveal an earlier age of amyloid beta (Aβ) onset compared to sporadic AD. Differences in amyloid accumulation rates between DS and sporadic AD populations have not been established.

METHODS: Participants with ≥ 3 [C-11]PiB scans (spanning > 6 years) and transitioning to Aβ+ were included, resulting in 20 DS and 23 neurotypical (NT) participants. Amyloid accumulation was compared using global standardized uptake value ratio (SUVR) for Aβ deposition, with individual growth rates (r) estimated using the logistic growth model (S U V R (t) = S U V R B L + K 1 + e - r (t - t 50) $SUVR\ (t) = SUV{{R}_
{BL}}
+ \frac{K}{
{1 + {{e}^
{ - r({t - {{t}_
{50}}
})
}}
}}
$).

RESULTS: The average growth rate in the DS cohort was 0.28 (0.08)/year versus 0.20 (0.08)/year for NT (p = . 002 $p = .002$), an increase of 40%.

DISCUSSION: Using individual longitudinal analyses, accelerated amyloid accumulation in DS is observed, This has important considerations for informing treatment trial design and monitoring beta-amyloid changes in future AD studies involving individuals with DS.

HIGHLIGHTS: Aβ accumulation rate was estimated using a logistic growth model. There was no overlap in the age of amyloid positivity between DS and NT cohorts. Participants with DS accumulate amyloid 40% faster than those with sporadic AD.},
}

Humans
*Down Syndrome/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
Male
Female
*Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism
Middle Aged
*Brain/diagnostic imaging/metabolism
Adult
Aged
Aniline Compounds
Thiazoles

@article {pmid40555646,
year = {2025},
author = {Wang, Q and Sun, X and Wu, X and Liu, J and Chang, C and Liu, Y and Xu, T and Liu, Q},
title = {An Ultrasensitive Wearable Nanosensor for Minimally Invasive Self-Screening of Alzheimer's Disease.},
journal = {Nano letters},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.nanolett.5c02255},
pmid = {40555646},
issn = {1530-6992},
abstract = {The rising global prevalence of Alzheimer's disease (AD) has emerged as a critical public health challenge, placing strain on families, communities, and healthcare systems. Despite advances in diagnostic methods, current techniques for early AD detection remain limited, often being invasive, costly, and impractical for regular use. Here, we report a fully integrated wearable nanosensor offering an easily accessible and user-friendly strategy for AD screening. This biosensing platform incorporates a microneedle-based interstitial fluid (ISF) sampling device and an ultrasensitive graphene field-effect transistor (GFET) chip, enabling rapid and precise detection of AD biomarkers. Furthermore, this nanosensor was successfully validated in transgenic murine models, demonstrating reliable differentiation between AD and non-AD mouse groups with high specificity. Overall, this study offers a promising alternative tool to the existing invasive and expensive techniques for the AD preliminary screening, paving the way for drug discovery, early diagnosis, and personalized treatment of AD.},
}

@article {pmid40555521,
year = {2025},
author = {Lokesh, M and Bandaru, LJM and Rajanna, A and Dhayal, VS and Challa, S},
title = {Microglial Dysfunction Mediated by Pb and Amyloid Beta Peptides as a Possible Mechanism of Neurotoxicity.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4839},
pmid = {40555521},
issn = {1099-1263},
support = {58/57/2012-BMS//Indian Council of Medical Research/ ; },
abstract = {This study delves into the inflammatory and degenerative impacts of lead (Pb) toxicity and amyloid beta peptides (Aβ-peptide 1-40 and Aβ-peptide 25-35) on brain cells, particularly by fostering M1 polarization in microglial cells and subsequent neuronal cell death, crucial in conditions like Alzheimer's disease. Microglia were exposed to IC50 concentrations of Pb, and Aβ-peptide 1-40 and Aβ-peptide 25-35 exhibited notable increases in intracellular ROS levels (32.95%) upon exposure to combinatorial treatments. Moreover, there was a significant decline in total antioxidant capacity to 69.57%, suggesting oxidative damage and compromised cellular defenses against stress, coupled with heightened glutamate levels (921.3 μM). Treatment with Pb alongside Aβ-peptide 1-40 and Aβ-peptide 25-35 also led to elevated intracellular calcium levels (33.83%) and increased production of pro-inflammatory cytokines IL-6 (5.54 pg/mL), TNF-α (5.8 pg/mL), and IFN-γ (13.52 pg/mL) and reduced levels of anti-inflammatory cytokines IL-10 (5.61 pg/mL) and IL-4 (14.46 pg/mL) in microglial cells compared with the control group. Furthermore, upregulation of NF-κB/p65 pathway-associated markers was observed, and when co-cultured with neuronal cells for 24 h, polarized microglia induced neuronal cell death (57.9%). These findings provide insights into the complex molecular mechanisms involved in lead-induced neurotoxicity and neurodegenerative disorders.},
}

@article {pmid40555519,
year = {2025},
author = {Gerasimov, E and Rakovskaya, A and Pchitskaya, E and Vlasova, O and Dahl, R and Bezprozvanny, I},
title = {A positive allosteric modulator of the SERCA pump rescues hippocampal neuronal circuits dysfunction and cognitive defects in a mouse model of Alzheimer's disease.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2337-24.2025},
pmid = {40555519},
issn = {1529-2401},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder that affects normal neuronal functioning, alters neuronal circuits activity and memory formation and storage. Disrupted neuronal calcium (Ca[2+]) signaling is one of the drivers of AD pathogenesis. Previously we suggested that positive allosteric modulators (PAMs) of the sarco/endoplasmic reticulum Ca[2+] ATPase (SERCA) pump may help to stabilize cytosolic Ca[2+] levels and exert neuroprotective effects in AD neurons. In the current manuscript we demonstrate synaptoprotective properties of several SERCA PAMs using an in vitro model of amyloid toxicity. Based on in vitro experiments, we selected the SERCA PAM NDC-9009 for in vivo evaluation in male and female 5xFAD transgenic mice model of Alzheimer's disease. Using the miniscope imaging technique, we observed hyperactivity and abnormal connectivity of hippocampal neuronal ensembles 5xFAD mice. We further discovered that the function of the hippocampal neuronal circuits in 5xFAD mice was normalized by NDC-9009 intraperitoneal administration. NDC-9009 intraperitoneal administration also rescued memory defects in 5xFAD mice as quantified by the fear conditioning behavioral test and significantly reduced accumulation of amyloid plaques in hippocampal region of these mice. The obtained results support the potential utility of NDC-9009 and other SERCA PAMs as lead molecules for development of disease-modifying treatments for AD and potentially other neurodegenerative disorders.Significance statement Alzheimer's disease (AD) is a significant medical and social burden, yet no treatment currently exists. One of the hallmarks of AD is disrupted Ca[2+] signaling, which contributes to neuronal dysfunction and degeneration. In the current study, we demonstrate the potential of the SERCA pump positive allosteric modulators (PAMs) as promising disease-modifying agents. Through an in vitro screening, we identified NDC-9009 as the most effective SERCA PAM, promoting robust cytosolic calcium clearance and exhibiting neuroprotective properties. Furthermore, using miniature fluorescence in vivo imaging, a significant restoration of hippocampal neuronal ensembles activity and cognitive function after chronic administration of NDC-9009 in the transgenic AD mouse model was demonstrated.},
}

@article {pmid40555242,
year = {2025},
author = {Maloney, EK and Bleakley, A and White, AJ},
title = {Alzheimer's and Dementia Research Coverage in News Media Outlets Consumed by Population Groups that Are Underrepresented on Alzheimer's and Dementia-Focused Research Registries.},
journal = {Research on aging},
volume = {},
number = {},
pages = {1640275251346851},
doi = {10.1177/01640275251346851},
pmid = {40555242},
issn = {1552-7573},
abstract = {A lack of diversity in Alzheimer's (AD) and dementia research is an important barrier to identifying strategies for prevention and treatment. Research suggests media coverage of AD/dementia research will familiarize people with the issue and motivate them to place more importance in the issue in general. This study explores how news media may inform groups that are under-represented in AD/dementia through coverage of the issue. A national survey identified the media outlets that were most often consumed and used for health information within target populations. Transcripts from these media outlets were content analyzed to examine AD/dementia coverage. The timeframe included the months before and after the US FDA's approval of the drug Aduhelm and the controversy surrounding it. Results highlight differences in under-represented groups' media consumption patterns and coverage of AD/dementia and indicates a failure to inform about an event that may have widespread effect on Medicare and AD/dementia research.},
}

@article {pmid40555059,
year = {2025},
author = {Faysal, M and Zehravi, M and Amin, MA and Rab, SO and Jahnavi, P and Arjun, UVNV and Gupta, JK and Billah, AAM and Vodeti, R and Prasad, PD and Aseri, SSS and Siddiqui, FA and Bin Emran, T},
title = {Clinical insights into the mechanisms of infectious microbes and microbiota in chronic neurologic and psychiatric diseases.},
journal = {Pathology, research and practice},
volume = {272},
number = {},
pages = {156090},
doi = {10.1016/j.prp.2025.156090},
pmid = {40555059},
issn = {1618-0631},
abstract = {Chronic neurologic and psychiatric diseases such as schizophrenia, depression, Parkinson's, and Alzheimer's are increasingly linked to infectious microorganisms and gut microbiota. This review explores how pathogenic microorganisms and microbial communities impact neuropsychiatric, neurodegenerative, and neuroinflammatory processes, highlighting the gut-brain axis' crucial communication network in influencing behavior and brain function. Infectious agents like bacteria, viruses, and fungi cause disease by causing neurotoxic reactions, disrupting the blood-brain barrier, and activating neuroinflammatory cascades. Gut dysbiosis impacts immunological homeostasis and neural transmission by altering the synthesis of metabolites from microorganisms, such as short-chain fatty acids and neurotransmitter precursors. Neurodegeneration and psychiatric diseases are influenced by molecular mechanisms such as toll-like receptor signaling, microglial activation, and mitochondrial dysfunction. This review highlights the potential of microbiota-targeted treatments such as probiotics, prebiotics, and microbiome transplantation as novel treatments for chronic diseases. Understanding the intricate interactions between infectious microorganisms, microbiota, and the central nervous system enables the formation of precision medicine strategies to challenge the rising incidence of neurologic and psychiatric diseases. Future research should explore causal relationships and identify specific microbial biomarkers to enhance early diagnosis, prevention, and personalized treatment plans.},
}

@article {pmid40554441,
year = {2025},
author = {Tu, H and Zhou, S and Lin, J},
title = {Combined Effects of Donepezil and Memantine on Behavioral and Psychological Symptoms, Cognitive Function, and Daily Living Abilities in Patients With Alzheimer's Disease.},
journal = {British journal of hospital medicine (London, England : 2005)},
volume = {86},
number = {6},
pages = {1-15},
doi = {10.12968/hmed.2024.1037},
pmid = {40554441},
issn = {1750-8460},
mesh = {Humans ; *Donepezil/administration & dosage/therapeutic use/adverse effects ; *Alzheimer Disease/drug therapy/psychology ; Male ; Female ; *Memantine/administration & dosage/therapeutic use/adverse effects ; Aged ; *Activities of Daily Living ; Retrospective Studies ; *Cognition/drug effects ; Quality of Life ; Drug Therapy, Combination ; Aged, 80 and over ; Nootropic Agents/administration & dosage ; Dose-Response Relationship, Drug ; Cholinesterase Inhibitors/administration & dosage ; },
abstract = {Aims/Background Combined with memantine, donepezil has a beneficial impact on the treatment of moderate to severe Alzheimer's disease (AD), but it can potentially increase the risk of adverse events. The aim of this study is to compare the effects of low-dose and high-dose donepezil combined with memantine on the behavioral and psychological symptoms, cognitive function, and daily living abilities of patients with moderate to severe AD, and to explore their safety. Methods This retrospective study includes 106 AD patients who received treatment in the Third People's Hospital of Fuyang from January 2022 to January 2024. The patients were grouped according to treatment regimen: patients receiving low-dose donepezil (5 mg/day) combined with memantine were included in the low-dose group (n = 45), and those receiving high-dose donepezil (10 mg/day) combined with memantine were included in the high-dose group (n = 61). The assessment results of behavioral and psychological symptoms, cognitive function, daily living ability, quality of life, sleep quality, as well as the occurrence of adverse reactions during treatment were obtained from electronic medical records for the two groups of patients before and after 24 weeks of treatment, and were compared using appropriate statistical tests. Results After 24 weeks of treatment, the scores of neuropsychiatric inventory (NPI) and behavioral pathology in Alzheimer's disease rating scale (BEHAVE-AD) were similar between the two groups (p > 0.05). The scores of Mini-Mental State Examination (MMSE) and Alzheimer's disease assessment scale-cognitive section (ADAS-Cog) were similar between the two groups (p > 0.05). The scores of activities of daily living (ADL) were comparable between the two groups (p > 0.05), and the low-dose group had significantly higher quality of life-Alzheimer's disease (QOL-AD) scores compared to the high-dose group (p < 0.05). The Pittsburgh sleep quality index (PSQI) scores of patients in the high-dose group were significantly higher than those before treatment and those in the low-dose group (p < 0.05). There was no statistically significant difference in PSQI scores between the low-dose group before and after treatment (p > 0.05). During the treatment period, the total incidence of adverse reactions in the low-dose group was significantly lower than that in the high-dose group (11.11% vs. 27.87%, p < 0.05). Conclusion Both 5 mg/day or 10 mg/day donepezil in combination with memantine holds the potential to improve behavioral and psychological symptoms, cognitive function and daily living abilities in patients with moderate-to-severe AD. In addition, high doses of donepezil may lead to decreased sleep quality in patients, increased risk of adverse reactions, and less improvement in quality of life than low doses.},
}

Humans
*Donepezil/administration & dosage/therapeutic use/adverse effects
*Alzheimer Disease/drug therapy/psychology
Male
Female
*Memantine/administration & dosage/therapeutic use/adverse effects
Aged
*Activities of Daily Living
Retrospective Studies
*Cognition/drug effects
Quality of Life
Drug Therapy, Combination
Aged, 80 and over
Nootropic Agents/administration & dosage
Dose-Response Relationship, Drug
Cholinesterase Inhibitors/administration & dosage

@article {pmid40554071,
year = {2025},
author = {Wang, F and Zhou, Q and Chen, Z and Xie, L and Zheng, N and Chen, Z and Sun, Q and Du, J and Lin, J and Li, B and Li, L},
title = {Cyclovirobuxine inhibits ferroptosis to mitigate Alzheimer disease in glutamate-induced SH-SY5Y cell: the role of the liquid-liquid phase separation of FTH1.},
journal = {Molecular pharmacology},
volume = {107},
number = {7},
pages = {100046},
doi = {10.1016/j.molpha.2025.100046},
pmid = {40554071},
issn = {1521-0111},
abstract = {Ferroptosis represents a distinct form of cell death that differentiates it from conventional apoptosis. Numerous studies have demonstrated that ferroptosis holds significant potential for elucidating neuronal damage in Alzheimer disease (AD). In addition, liquid-liquid phase separation has emerged as a significant biological process in recent years. It plays a crucial role in the regulation of various proteins in vivo and is closely associated with ferroptosis. Meanwhile, nuclear factor erythroid 2-related factor 2 (Nrf2) serves as a crucial signaling pathway in ferroptosis and plays a significant role in regulating many key components of the ferroptosis pathway. In addition, an increasing volume of research is being conducted on natural medicines aimed at enhancing the treatment of AD. Cyclovirobuxine (Cyc) is an alkaloid compound extracted from the traditional Chinese medicinal plant, boxwood. It has demonstrated therapeutic potential in the treatment of neurodegenerative diseases. Therefore, in this study, we established an AD cell model using glutamate-induced SH-SY5Y. In glutamate-induced SH-SY5Y cells, Cyc treatment significantly improved mitochondrial function and effectively inhibited lipid peroxidation and restored the downregulation of FTH1 levels induced. Furthermore, Cyc treatment activated the Nrf2 signaling pathway, significantly elevated the nuclear levels of Nrf2, and inhibited both iron deposition and lipid peroxidation. Cyc treatment conferred resistance to ferroptosis in erastin-stimulated SH-SY5Y cells, wherein the Nrf2 signaling pathway and FTH1 protein play crucial roles. The collective findings presented here underscore the protective mechanism of action of Cyc in AD and emphasize its potential as a therapeutic agent for AD treatment. SIGNIFICANCE STATEMENT: It reveals at the cellular level the mechanism by which cyclovirobuxine improves Alzheimer disease through the inhibition of ferroptosis, providing a novel approach and strategy for the treatment of patients with Alzheimer disease.},
}

@article {pmid40554062,
year = {2025},
author = {Ma, R and Wang, S and Cui, YL and Zhang, H and Chen, X and Xie, J and Li, Y},
title = {Therapeutic role of caveolin family in stem cell fate and development for management of chronic degenerative diseases: A scientometric study to an in-depth review.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.06.034},
pmid = {40554062},
issn = {2090-1224},
abstract = {BACKGROUND: Caveolins (CAV), a family of integral membrane proteins, are involved in regulating stem cell fate, which are critical for tissue repair and regeneration. Drawing from scientometric studies and comprehensive research, this review investigates the mechanisms by which CAV regulates stem cell fate can improve the efficiency and accuracy of stem cell therapy in treating chronic degenerative diseases (CDD). For instance, CAV1 inhibits neuronal differentiation of neural stem/progenitor cells (NSCs/NPCs) by downregulating VEGF, p44/42MAPK phosphorylation and NeuroD1 signaling pathway following ischemic stroke, while CAV3 interacts with MG53 to enhance the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) in diabetic wound healing by activating the eNOS/NO signaling pathway.

AIM OF REVIEW: Our review aims to elaborate the impact of CAV on diverse stem cell populations and regulatory mechanisms, as well as point out novel insights brought by CAV and stem cell therapy in the management of CDD, such as stroke, Alzheimer's disease (AD), Parkinson's disease (PD), diabetes, pulmonary arterial hypertension (PAH), breast cancer and liver cancer.

Based on scientometrics studies, this review synthesizes current analyses of the CAV family's role in determining the fate of various stem cell populations, thereby providing new perspectives for the prevention and treatment of CDD.},
}

@article {pmid40553197,
year = {2025},
author = {Unal, O and Akgun-Unal, N and Baltaci, AK},
title = {Unveiling mysteries of aging: the potential of melatonin in preventing neurodegenerative diseases in older adults.},
journal = {Biogerontology},
volume = {26},
number = {4},
pages = {125},
pmid = {40553197},
issn = {1573-6768},
mesh = {Humans ; *Melatonin/therapeutic use ; *Neurodegenerative Diseases/prevention & control/metabolism ; *Aging/drug effects/metabolism ; Aged ; Antioxidants/therapeutic use ; Animals ; Oxidative Stress/drug effects ; *Neuroprotective Agents/therapeutic use ; },
abstract = {Neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, result in a substantial health problem for the elderly, marked by ongoing neuronal degeneration and a deterioration in mental faculties. These disorders are frequently linked to oxidative stress, problems with mitochondria, and persistent inflammation in the brain, which worsen neuronal damage. The neurohormone melatonin, primarily secreted by the pineal gland, has gained recognition as a promising therapeutic agent due to its antioxidant, anti-inflammatory, and neuroprotective effects. Melatonin's functions extend beyond its regulation of circadian rhythms, as research has demonstrated its ability to remove free radicals, improve mitochondrial performance, and adjust immune system responses, ultimately reducing the progression of neurodegenerative disease. Research findings from preclinical and clinical trials imply that taking melatonin supplements could lead to improved cognitive abilities, slower disease progression, and an overall better quality of life for elderly individuals suffering from neurodegenerative conditions. The mechanisms through which melatonin acts, the best dosage, and its long-term effectiveness are still being researched. This review underscores the potential benefits of melatonin as a supplementary treatment for neurodegenerative disorders in older adults, stressing the necessity for additional studies to confirm its efficacy and standardize its use in treatment plans.},
}

Humans
*Melatonin/therapeutic use
*Neurodegenerative Diseases/prevention & control/metabolism
*Aging/drug effects/metabolism
Aged
Antioxidants/therapeutic use
Animals
Oxidative Stress/drug effects
*Neuroprotective Agents/therapeutic use

@article {pmid40552995,
year = {2025},
author = {Shepherd, TM},
title = {Imaging the Treatment of Alzheimer Disease: 2030 Could Look Very Different.},
journal = {Radiology},
volume = {315},
number = {3},
pages = {e251704},
doi = {10.1148/radiol.251704},
pmid = {40552995},
issn = {1527-1315},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy ; Brain/diagnostic imaging ; *Diagnostic Imaging ; },
abstract = {"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content.},
}

Humans
*Alzheimer Disease/diagnostic imaging/therapy
Brain/diagnostic imaging
*Diagnostic Imaging

@article {pmid40552707,
year = {2025},
author = {Siriwardhana, C and Gunaratnam, B and Kulasekera, KB},
title = {Personalized Treatment Selection for Multivariate Ordinal Scale Outcomes and Multiple Treatments.},
journal = {Pharmaceutical statistics},
volume = {24},
number = {4},
pages = {e70023},
doi = {10.1002/pst.70023},
pmid = {40552707},
issn = {1539-1612},
support = {R03AG075034/AG/NIA NIH HHS/United States ; 2U54MD007601-36/MD/NIMHD NIH HHS/United States ; },
mesh = {Humans ; *Precision Medicine/methods/statistics & numerical data ; Alzheimer Disease/drug therapy ; Treatment Outcome ; Computer Simulation ; Models, Statistical ; Clinical Trials as Topic/statistics & numerical data/methods ; Cystic Fibrosis/drug therapy ; Multivariate Analysis ; },
abstract = {In this study, we present an innovative approach for tailoring treatment selection on an individualized basis in the presence of correlated multiple responses, particularly those measured on ordinal scales, including binary responses. Our methodology involves the utilization of rank lists for treatments, generated from probabilities of observing responses of higher order than each level of the ordinal outcome, conditional on patient covariate measurements. We introduce a rank aggregation technique designed to amalgamate multiple lists of ranks, allowing for correlations both within these lists and among elements within each list. Our approach is versatile, accommodating any number of treatments and responses, and is applicable across a wide range of models. Our method offers flexibility by allowing the integration of response weights, enabling customization based on patient and clinician preferences on an individual case basis for optimal treatment decisions. To evaluate the performance of our proposed method in finite samples, we conducted a simulation study. Furthermore, we provide two illustrative examples using data from clinical trials on Cystic Fibrosis and Alzheimer's Disease, demonstrating the application of our proposed procedure in real-world scenarios.},
}

Humans
*Precision Medicine/methods/statistics & numerical data
Alzheimer Disease/drug therapy
Treatment Outcome
Computer Simulation
Models, Statistical
Clinical Trials as Topic/statistics & numerical data/methods
Cystic Fibrosis/drug therapy
Multivariate Analysis

@article {pmid40552323,
year = {2025},
author = {Wang, X and Li, Z and Ma, B and Jia, Q},
title = {Research progress on microglial pyroptosis and inflammasomes: a comprehensive analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1582579},
pmid = {40552323},
issn = {1663-4365},
abstract = {BACKGROUND: Microglial pyroptosis and inflammasome activation play critical roles in neurodegenerative diseases, especially Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). In recent years, substantial attention has been directed toward elucidating their underlying mechanisms, diagnostic approaches, and prognostic implications. This study aimed to analyze the current research landscape, hotspots, and trends in this field.

METHODS: Articles published over the past decade on microglial pyroptosis and inflammasomes were retrieved from the Web of Science Core Collection (WoSCC) database. A comprehensive analysis was conducted, and high-impact articles were examined in depth.

RESULTS: A total of 958 articles were included. Among these, 664 originated from China, which also had the highest H-index (68), followed by 147 articles from the United States, with an H-index of 48 and the highest centrality (0.68). Southern Medical University (China) was the leading institution in terms of articles (47) and achieved the highest H-index (19). Journal of Neuroinflammation published the most articles (59) in this field. High-impact studies predominantly focused on the roles of microglial pyroptosis and inflammasomes in neurodegenerative diseases, neuroinflammation and therapeutic intervention strategies. Keywords such as "depression," "cell death," "recovery," and "pathogenesis" emerged as research hotspots over the past 3 years.

CONCLUSION: Microglial pyroptosis and inflammasome activation have become research hotspots in neurodegenerative disease, with China and the United States leading in article output and research influence in this field. Southern Medical University (China) is the most influential institution, and the Journal of Neuroinflammation is the most prolific journal. Current research hotspots emphasize elucidating the pathological mechanisms of microglial pyroptosis and inflammasome activation in neurodegenerative diseases, especially in AD, PD, and MS, and exploring potential therapeutic strategies such as MCC950, quercetin, MicroRNA-7, and melatonin. Future studies are expected to focus on mechanism elucidation, disease specificity, dynamic regulation, targeted interventions, and clinical translation to enhance treatment outcomes and prognosis for neurological disorders.},
}

@article {pmid40552150,
year = {2025},
author = {Ordaz, DA and Gupta, K and Bota, DA},
title = {The role of Poly-ADP ribose polymerase (PARP) enzymes in chemotherapy-induced cognitive impairments - parallels with other neurodegenerative disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1615843},
pmid = {40552150},
issn = {1663-9812},
abstract = {Poly (ADP-ribose) polymerase (PARP) enzymes are critical in repairing DNA damage induced by chemotherapy and/or radiation. Due to PARP's role in DNA repair, inhibiting PARP leads to genomic instability and accumulation of damaged cells in cell cycle arrest. Previous studies have shown that PARP1 activation contributes to the development of various malignant disorders, and using PARP inhibitors is a promising intervention in these diseases. However, PARP activation is also common in neurological and inflammatory disorders. PARP inhibitors were studied in preclinical models of neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's Disease (AD). In neurodegenerative disorders like AD, activated PARP1 induces Aβ and forms Tau tangles, worsening cognitive symptoms. PARP inhibitors are currently used in combination therapy with chemotherapy drugs, including cisplatin and temozolomide, which are all described as having significant rates of central and peripheral nervous system side-effects, raising the potential question of using PARP inhibition not only as a cancer treatment but as an approach to mitigate the toxicity of the cancer drugs. This review will summarize evidence for the potential use of PARP inhibitors for neurologic disorders and discuss future prospects of how PARP inhibitors could be repurposed as neuroprotective agents against the cognitive complications of chemotherapeutic drugs.},
}

@article {pmid40551989,
year = {2025},
author = {Li, P and Gao, Y and Tao, Z and Mu, Z and Du, S and Zhao, X},
title = {PANoptosis: Cross-Talk Among Apoptosis, Necroptosis, and Pyroptosis in Neurological Disorders.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {8131-8140},
pmid = {40551989},
issn = {1178-7031},
abstract = {Cell death mechanisms play a critical role in organismal development and homeostasis, primarily categorized into energy-dependent programmed cell death (PCD) and energy-independent necrotic cell death. PCD, regulated through various forms such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagic cell death, is essential for maintaining tissue stability and eliminating abnormal cells. Dysregulation of PCD is associated with numerous diseases, including cancer and neurodegenerative disorders. Recent studies have revealed extensive crosstalk and coordination among classical cell death pathways, leading to the identification of a novel programmed cell death mode termed PANoptosis. PANoptosis involves the dynamic assembly of the PANoptosome complex, which simultaneously activates apoptosis, pyroptosis, and necroptosis pathways in response to pathogen infection or tissue damage. In neurological diseases, PANoptosis exhibits dual roles: it can eliminate pathogen-infected cells but may also exacerbate neuroinflammation and neuronal death, contributing to the progression of neurodegenerative disorders. This review critically evaluates the molecular mechanisms of PANoptosis, its dual roles in neurological diseases (eg, Alzheimer's disease, Parkinson's disease, stroke, and glioma), and potential therapeutic strategies targeting PANoptosis, including small-molecule inhibitors, genome editing, and delivery technologies. By addressing conflicting evidence and outstanding questions, this review aims to provide a comprehensive framework for future research and clinical applications. Future research should focus on elucidating the molecular regulatory networks of PANoptosis, developing specific inhibitors, and advancing clinical applications to provide novel insights into the precise treatment of neurological diseases.},
}

@article {pmid40551964,
year = {2025},
author = {Beasley, BW},
title = {Why testing and diagnosis for Alzheimer's disease are mission critical.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70126},
pmid = {40551964},
issn = {2352-8737},
abstract = {The author, a physician who has younger-onset Alzheimer's disease (AD), recounts his recent lunch with a former coworker who has had a stroke. The author makes the point that because we now have an effective treatment for AD, and phosphorylated tau217 is a sensitive and specific screening test for AD, we should advocate for its usage in Medicare Wellness Visits, given that the adage "Time Is Brain" is just as apropos for AD as it has been in stroke care. However, at this time, Medicare is not paying for the lab test.},
}

@article {pmid40551529,
year = {2025},
author = {Shahrukh, M and Ahmad, S and Zaafar, M and Hasan, N and Ahmad, FJ},
title = {Management of Alzheimer's Disease With Nanotechnological Interventions and Novel Therapeutics.},
journal = {Drug development research},
volume = {86},
number = {5},
pages = {e70120},
doi = {10.1002/ddr.70120},
pmid = {40551529},
issn = {1098-2299},
support = {//The author would like to acknowledge the CSIR, for providing the CSIR-JRF fellowship to the first author (File No. 09/0591(16126)/2022-EMR-I). The author is also thankful to the Department of Science and Technology (DST), Govt of India for providing infrastructure under the DST-FIST program./ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; Drug Delivery Systems/methods ; Animals ; Genetic Therapy/methods ; Blood-Brain Barrier/metabolism ; Nanotechnology/methods ; Immunotherapy/methods ; Stem Cell Transplantation/methods ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by cognitive deterioration, β-amyloid plaque buildup, intracellular tangles, and significant neuronal loss. The increasing prevalence of AD, along with its substantial economic burden, underscores the urgent need for effective therapeutic strategies in the near future. The challenge is early diagnosis and management, hindered by the lack of reliable biomarkers. Currently, there is no definitive cure for AD. Attaining improved therapeutic outcomes necessitates delivering optimal drug concentrations to the central nervous system (CNS) by effectively penetrating the blood-brain barrier (BBB). Recently, nanotechnology has emerged as a promising approach to address this challenge, enhancing brain-targeted drug delivery while highlighting recent advancements and future potential. Additionally, novel targeted therapies such as genetic therapeutics, stem cell therapy, and immunotherapy approaches overcome AD-based challenges, enhance treatment efficacy, and improve patient compliance. This review highlights recent advancements in the treatment of AD, focusing on nanotechnology-based drug delivery systems, and also explores genetic therapeutics, stem cell therapy, and immunotherapy approaches. Overall, the review provides a comprehensive overview of these therapeutic approaches, shedding light on the evolving landscape of AD treatment and the challenges that lie ahead.},
}

*Alzheimer Disease/therapy/drug therapy
Humans
Drug Delivery Systems/methods
Animals
Genetic Therapy/methods
Blood-Brain Barrier/metabolism
Nanotechnology/methods
Immunotherapy/methods
Stem Cell Transplantation/methods

@article {pmid40551140,
year = {2025},
author = {Rehman, H and Yan, S and Saggu, S and Aida, M and Zhang, F and Shu, Y and Jones, A and Trang, A and Dew, E and Zhi, W and Claeboe, ET and Baucum, AJ and Wu, G and Jiao, K and Wang, Q},
title = {The PKCι-β-arrestin2 axis disrupts SORLA retrograde trafficking, driving its degradation and amyloid pathology in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {76},
pmid = {40551140},
issn = {1750-1326},
mesh = {*Alzheimer Disease/metabolism/pathology ; Animals ; Humans ; Mice ; *beta-Arrestin 2/metabolism ; *Membrane Transport Proteins/metabolism ; Protein Transport/physiology ; *LDL-Receptor Related Proteins/metabolism ; *Protein Kinase C/metabolism ; Disease Models, Animal ; Neurons/metabolism ; Amyloid beta-Peptides/metabolism ; Signal Transduction/physiology ; },
abstract = {BACKGROUND: Variants of SORL1 have been associated with both late and early onset of Alzheimer's disease (AD). SORL1 encodes the sorting-related receptor with A repeat (SORLA) protein, which belongs to the VPS10 receptor family. SORLA protects against AD pathogenesis through its sorting function, and reduced SORLA levels have been consistently observed in sporadic AD. Although the importance of SORLA in AD pathogenesis is well recognized, how it can be targeted for AD treatment remains to be established, owing to the inadequate understanding of its regulation by intracellular signaling.

METHODS: We employed combined biochemical, cell biological, and pharmacological approaches to investigate how SORLA trafficking and stability are regulated. Additionally, we used an AD mouse model, postmortem tissue samples, and iPSC-derived neurons to examine the functional outcomes of this regulation.

RESULTS: We identified a novel direct interaction between SORLA and β-arrestin2 (βARR2), which impedes the interaction of SORLA with the retromer complex, thus reducing the retrograde trafficking of SORLA. βARR2 promotes the interaction between SORLA and the ESCRT0 complex, leading to the lysosomal localization and degradation of SORLA. We also found that PKCι/λ induces SORLA phosphorylation and enhances its interaction with βARR2, promoting SORLA degradation. Importantly, blocking PKCι/λ with auranofin disrupts the SORLA-βARR2 interaction, elevates SORLA levels, decreases amyloidogenic processing of APP, and improves cognition in the App[NL-G-F/NL-G-F] AD mouse model. Furthermore, PKCι is hyperactive in human AD brains, and auranofin reduces Aβ production in AD iPSC-derived neurons through increasing SORLA levels.

CONCLUSION: Our study reveals the PKCι/λ-βARR2 axis as a key molecular mechanism that disrupts SORLA retrograde trafficking and drives its degradation. Our findings represent the first evidence that SORLA levels can be pharmacologically manipulated through blocking PKCι/λ to reduce Aβ production and alleviate AD-related phenotypes. Notably, repurposing auranofin, an FDA-approved drug for rheumatoid arthritis, may offer the potential for AD treatment.},
}

*Alzheimer Disease/metabolism/pathology
Animals
Humans
Mice
*beta-Arrestin 2/metabolism
*Membrane Transport Proteins/metabolism
Protein Transport/physiology
*LDL-Receptor Related Proteins/metabolism
*Protein Kinase C/metabolism
Disease Models, Animal
Neurons/metabolism
Amyloid beta-Peptides/metabolism
Signal Transduction/physiology

@article {pmid40551105,
year = {2025},
author = {Sun, X and Liu, H and Li, W and Li, L and Tian, Q and Cao, Q and Meng, Y and Shen, Y and Che, F and Chiu, JC and Yu, J and Hammock, BD},
title = {The soluble epoxide hydrolase inhibitor TPPU alleviates Aβ-mediated neuroinflammatory responses in Drosophila melanogaster and cellular models of alzheimer's disease.},
journal = {Journal of inflammation (London, England)},
volume = {22},
number = {1},
pages = {25},
pmid = {40551105},
issn = {1476-9255},
support = {(201919010)//This work was supported by a grant from Linyi Science and Technology Development Program, China./ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease, and its pathogenesis is closely associated with neuroinflammation. The control of neuroinflammation in AD is the focus of current research. soluble epoxide hydrolase (sEH) protein is increased in the brain tissues of patients with AD and has been targeted by multiple genome wide association studies as a prime target for treating AD. Since sEH induces nerve inflammation by degrading epoxyeicosatrienoic acids (EETs), application of sEH inhibitor and sEH gene knockout are effective ways to improve the bioavailability of EETs and inhibit or even resolve neuroinflammation in AD. 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a potent sEH inhibitor that has been shown to be effective in preclinical animal models of a variety of chronic inflammatory diseases. This study aims to further explore whether TPPU can alleviate AD neuroinflammation.

METHODS: We established an Aβ42-transgenic Drosophila melanogaster model using the galactose-regulated upstream promoter element 4 (GAL4) / upstream active sequence (UAS) expression system and investigated the protective and anti-neuroinflammatory effects of TPPU against Aβ toxicity. We detected behavioral indexes (survival time, crawling ability, and olfactory memory) and biochemical indexes malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in brain tissues of Aβ42 transgenic flies. Finally, we explored the anti-neuroinflammatory effect of TPPU and its possible mechanism by stimulating cocultures of human SH-SY5Y cells and HMC3 cells with Aβ(25-35) to model neuronal cell inflammation, and evaluated the cells by fluorescence microscopy, ELISA, Western Blot, and Real-time PCR.

RESULTS: We found that TPPU improved the survival time, crawling ability, and olfactory memory of Aβ42-transgenic flies. We also observed reduction of MDA content and elevation of SOD activity in the brain tissues of these flies. In human cell models, we found that TPPU improved cell viability, reduced cell apoptosis, decreased lipid oxidation, inhibited oxidative damage, thus playing a neuroprotective role. The inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-18 (IL-18) were downregulated, and the mRNA expression of the M2 microglia markers CD206 and SOCS3 were upregulated by TPPU; thus, TPPU inhibited neuroinflammatory responses. TPPU exerted neuroprotective and anti-inflammatory effects by decreasing the protein expression of the sEH-encoding gene EPHX2 and increasing the levels of 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-epoxyeicosatrienoic acid (14,15-EET). The inhibitory effect of TPPU on Aβ(25-35)-mediated neuroinflammation was associated with inhibition of the toll like receptor 4 (TLR4)/nuclear transcription factor-κB (NF-κB) pathway and p38 mitogen activated protein kinases (MAPK)/NF-κB pathway.

CONCLUSIONS: We report that the sEH inhibitor TPPU exerts neuroprotective and anti-neuroinflammatory effects in AD models, and it is expected that this drug could potentially be used for the prevention and treatment of AD.},
}

@article {pmid40550741,
year = {2025},
author = {Loi, SM and Kang, MJ},
title = {Donanemab: The dawn of disease-modifying treatment for Alzheimer's disease in Australia.},
journal = {Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists},
volume = {},
number = {},
pages = {10398562251355157},
doi = {10.1177/10398562251355157},
pmid = {40550741},
issn = {1440-1665},
abstract = {On 22 May 2025, the Therapeutic Goods Administration (TGA) announced that the anti-amyloid monoclonal antibody donanemab (Eli Lilly, Kisunla) was approved in Australia for the treatment of Alzheimer's disease (AD). This has been heralded by some as a breakthrough for the treatment of AD, reflecting a turning point from symptomatic treatments to disease-modifying therapies. Psychiatrists should understand this scientific context, as it underpins both the hope and the limits of what donanemab can achieve. The roll-out of disease-modifying treatment comes with significant challenges but also provides a unique opportunity to improve care for people with AD and other dementias.},
}

@article {pmid40550256,
year = {2025},
author = {Gahr, M and Merz, B},
title = {[Trazodone in psychogeriatric care].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2600-3773},
pmid = {40550256},
issn = {1439-3522},
abstract = {Trazodone is a dual serotonergic antidepressant with insignificant anticholinergic effects. It features sedative, hypnotic and anxiolytic effects in lower and antidepressive effects in higher doses. Its tolerability is good and the most important adverse drug reactions are orthostatic hypotension, drowsiness/sedation with increased risk of falls, dose-dependent moderate QTc prolongation with the risk of ventricular arrhythmias and priapism. Trazodone has evidence-based efficacy in elderly patients with depression and normal cognitive functioning, and there is evidence of antidepressive efficacy of trazodone also in patients with depression and dementia/cognitive dysfunction. In patients with dementia and sleep disturbances, trazodone improves sleep efficiency and increases total nocturnal sleep time. Although there is some evidence of efficacy of trazodone in the treatment of behavioral and psychological symptoms of dementia, particularly agitation, and trazodone is explicitly recommended for treatment of motor unrest in frontotemporal dementia, the evidence for this is rather weak. Results from studies in animal models indicate neuroprotective effects of trazodone by inhibition of overactivation of signalling in the unfolded protein response (UPR) which is typical of some neurodegenrative diseases. It was demonstrated that regular trazodone use is associated with delayed cognitive decline in humans with a diagnosis of Alzheimer's dementia. However, it is currently unclear if trazodone features significant neuroprotective effects in humans.},
}

@article {pmid40550228,
year = {2025},
author = {Tiwari, A and Singh, B and Singh, GK and Meena, J and Agrawal, AK and Kumar, S and Modi, G},
title = {Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.5c00096},
pmid = {40550228},
issn = {2576-6422},
abstract = {Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.},
}

@article {pmid40549373,
year = {2025},
author = {Clocchiatti-Tuozzo, S and Rivier, CA and Renedo, D and Huo, S and de Havenon, A and Hawkes, MA and Gilmore, E and Schwamm, LH and Sheth, KN and Gill, TM and Falcone, GJ},
title = {APOE ε4 and Risk of Intracranial Hemorrhage in Patients With Atrial Fibrillation Taking Apixaban.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.0182},
pmid = {40549373},
issn = {2168-6157},
abstract = {IMPORTANCE: The APOE ε4 variant is causally linked to cerebral amyloid angiopathy and is a risk factor for intracranial hemorrhage (ICH) among warfarin-treated patients with atrial fibrillation. Nevertheless, its impact on those treated with apixaban remains unknown.

OBJECTIVE: To test the hypothesis that APOE ε4 allele carriership is associated with an increased risk of ICH in patients with atrial fibrillation taking apixaban.

This cohort study involved data from the All of Us Research Program, a longitudinal, population-based study in the United States. Inclusion criteria were age older than 50 years, history of atrial fibrillation, and anticoagulation with apixaban. Participants with a history of ischemic stroke or ICH were excluded. Up to 3 years of follow-up data were available. Data were collected from 2017 to 2022 and analyzed from November 2023 to December 2024.

EXPOSURE: APOE ε2, ε3, and ε4 were ascertained using variants rs429358 and rs7412. APOE ε4 was modeled dichotomously (noncarriers [no alleles] vs carriers [1 or 2 alleles]).

MAIN OUTCOMES AND MEASURES: Incident ICH, including any new intraparenchymal, subdural, or subarachnoid hemorrhage after initiation of apixaban therapy.

RESULTS: Of 413 477 All of Us participants, 2038 were eligible. Their mean (SD) age was 71 (9) years; 918 (45%) were female, 1120 (55%) were male, and 1710 (83%) had European ancestry. Among these participants, 483 (23.7%) were carriers of at least 1 APOE ε4 allele. After a median follow-up of 2.9 years, 26 participants sustained an ICH (cumulative incidence, 1.5%; 95% CI, 1.0%-2.2%), of whom 12 (cumulative incidence, 3.1%; 95% CI, 1.7%-5.3%) were carriers and 14 (cumulative incidence, 1%; 95% CI, 0.6%-1.7%) were noncarriers (P = .007). Multivariable Cox proportional hazard models confirmed this association: compared with noncarriership, APOE ε4 carriership was associated with a 3-fold increase in the risk of ICH (hazard ratio, 3.07; 95% CI, 1.42-6.65). APOE information improved the discrimination of risk prediction scores (C statistic of 0.74 and 0.68 for models with and without APOE, respectively; P = .03).

CONCLUSIONS AND RELEVANCE: Further research is needed to evaluate whether cerebral amyloid angiopathy mediates the observed association and whether APOE e4 information improves clinical decision-making about anticoagulation therapy in patients with atrial fibrillation. The latter is important now that APOE information is used in clinical settings to guide antiamyloid treatment for Alzheimer disease and has been returned to millions of persons by direct-to-consumer genotyping companies.},
}

@article {pmid40549157,
year = {2025},
author = {Chen, F and Chen, Y and Feng, S and Chen, H and Deng, L and Ma, F and Ke, Q and Liang, Q and Chen, J and Peng, X and Lu, J and Liu, Y and Xie, Y and Cao, H and Sun, Y and Wu, W and Cui, L and Wang, Y},
title = {APOE4 triggers dysregulated synaptic vesicle release by disrupting SNARE complex assembly.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {82},
number = {1},
pages = {248},
pmid = {40549157},
issn = {1420-9071},
support = {82071190//National Natural Science Foundation of China/ ; 82101269//National Natural Science Foundation of China/ ; 82301611//National Natural Science Foundation of China/ ; 2022A1515010593//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010179//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2024A1515012844//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2024A1515011464//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022M710848//China Postdoctoral Science Foundation/ ; 2023//Open Fund of Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases/ ; GCC2021010//Affiliated Hospital of Guangdong Medical University High Level talent research Launch project/ ; },
mesh = {*Synaptic Vesicles/metabolism ; *SNARE Proteins/metabolism ; Animals ; Vesicle-Associated Membrane Protein 2/metabolism ; *Apolipoprotein E4/metabolism/genetics ; Humans ; Mice ; Synaptic Transmission ; Rats ; Apolipoprotein E3/metabolism/genetics ; Protein Binding ; HEK293 Cells ; },
abstract = {The ε4 allele of the Apolipoprotein E (APOE) gene is an important genetic risk factor for several neurodegenerative diseases, while the common pathogenic mechanism is still unclear. Impaired synaptic transmission is one of the common pathogenic features of neurodegenerative diseases. By using proteomics analysis, co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assay, we demonstrated that APOE interacts with VAMP2, a core component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, in an APOE4 > APOE3 manner. Further in vitro and in vivo results suggest that APOE4 blocks SNARE complex assembly, which is likely driven by liquid-liquid phase separation (LLPS), negatively regulating synaptic vesicle release. Our study shows that APOE4 negatively regulates synaptic vesicle release by blocking the soluble SNARE complex assembly. Our data shed a light on how APOE polymorphism contributes to the risk for neurodegenerative diseases, and provides a theoretical basis for the future APOE targeted treatment of neurological diseases.},
}

*Synaptic Vesicles/metabolism
*SNARE Proteins/metabolism
Animals
Vesicle-Associated Membrane Protein 2/metabolism
*Apolipoprotein E4/metabolism/genetics
Humans
Mice
Synaptic Transmission
Rats
Apolipoprotein E3/metabolism/genetics
Protein Binding
HEK293 Cells

@article {pmid40548968,
year = {2025},
author = {Müller, DJ and Freitag, CM and Heilbronner, U and Nöthen, MM and Perneczky, R and Rietschel, M and Schulte, EC and Deckert, J and , },
title = {[Genetically informed treatment in psychiatry: new dynamics through APOE and antibody treatment of Alzheimer's disease].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {40548968},
issn = {1433-0407},
abstract = {The European Medicines Agency has recommended testing for the ApoE-genotype prior to treatment of Alzheimer's disease with Lecanemab. The drug approval is limited to patients who are not homozygous for the ApoE epsilon 4 allele. This is to reduce the risk of undesired adverse effects in the patients treated with Lecanemab. With this recommendation for the first time a psychiatric therapy will be genetically informed.},
}

@article {pmid40547330,
year = {2025},
author = {Snider, BJ and Biffi, A and Bozeat, S and Clevenger, C and Farrar, G and Gitelman, D and Kolster, R and Mattke, S and Mielke, M and Mukherjee, D and Murphy, J and Okhravi, H and Rabinovici, GD and Rentz, D and Soria, J and Synder, H and Walker, G and Mahinrad, S and Carrillo, MC and Weber, CJ},
title = {System readiness and the patient care pathway for Alzheimer's disease diagnosis and treatment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70094},
pmid = {40547330},
issn = {2352-8737},
abstract = {Promising therapeutic interventions that target the underlying pathophysiology are changing the landscape of Alzheimer's disease (AD) research. The AD care pathway must be transformed to meet the challenge of bringing these new therapies to the increasing number of people living with AD within the existing healthcare framework. Challenges include identifying patients who may benefit from treatment interventions early in the course of the disease, ensuring that diagnostic tools are accessible and accurate, and developing capabilities to monitor the effectiveness of interventions over time. These challenges must be addressed at all levels, from primary care settings to tertiary treatment centers; this will require collaborative efforts between health systems, drug manufacturers, and research institutions to navigate this evolving landscape and ensure system readiness for patients and their families with AD. The Spring 2024 Alzheimer's Association Research Roundtable (AARR) meeting gathered industry representatives and clinicians to discuss insights, challenges, and solutions that will help researchers and health systems identify patients in the early stages of AD and deliver emerging therapies efficiently and safely. In this paper, we provide highlights from the Spring 2024 AARR meeting.},
}

@article {pmid40547328,
year = {2025},
author = {Di Caro, V and Cho, E and North, HA and Caldwell, J and Pandey, K and Duong, D and Grundman, M and de Haan, W and Vijverberg, EG and Teunissen, CE and Caggiano, AO and Seyfried, NT and Hamby, ME},
title = {Identification of cerebrospinal fluid pharmacodynamic biomarkers and molecular correlates of brain activity in a Phase 2 clinical trial of the Alzheimer's disease drug candidate CT1812.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70119},
pmid = {40547328},
issn = {2352-8737},
abstract = {INTRODUCTION: CT1812 (zervimesine) is an orally dosed modulator of the sigma-2 receptor (S2R) currently in clinical development for the treatment of Alzheimer's disease (AD). CT1812 has been shown in preclinical and early clinical trials to selectively prevent and displace binding of amyloid beta oligomers from their synaptic receptors and has improved cognitive function in animal models of AD.

METHODS: SEQUEL (NCT04735536) is a completed Phase 2, randomized, placebo-controlled 4-week crossover trial in adults with mild-to-moderate AD that investigated the effect of CT1812 on safety, synaptic function using quantitative electroencephalography (qEEG), and biomarkers. CT1812 improved established qEEG markers of spontaneous brain activity, suggesting improved neuronal and synaptic function. In the present study, cerebrospinal fluid (CSF)-based tandem mass tag mass spectrometry (TMT-MS) was performed on participant samples to investigate proteomic effects and identify potential biomarkers of CT1812.

RESULTS: Biomarkers found through proteomics analyses to be significantly differentially abundant in CT1812- versus placebo-treated participants supported pathway engagement and proof of mechanism for CT1812. Impacted proteins support a role for CT1812 at synapses, in vesicle trafficking, and in lipoprotein biology. Biomarkers correlated with the previously reported improvements in qEEG-based functional connectivity (inferred through alpha band Amplitude Envelope Correlations) with CT1812 treatment were also identified and may be potential early surrogate biomarkers of efficacy for CT1812. The processes and functions supported by biomarkers were congruent with those previously revealed in CSF proteomics analyses from phase 1 and 2 AD clinical trials with CT1812.

DISCUSSION: After 1 month of treatment, the identification of biomarkers supporting pathway engagement, the replication of biomarker findings from prior trials, and the discovery of molecular correlates of improved functional connectivity with CT1812 treatment bolster support for and expound upon the mechanism of action for CT1812 in displacing Aβ oligomers at neuronal synapses, as well as underscores the CT1812 relevance to AD.

HIGHLIGHTS: Exploratory proteomics identified candidate CSF biomarkers of CT1812 in SEQUEL.Molecular correlates of functional brain connectivity (qEEG) were identified.Proteins impacted by 1 month CT1812 treatment support target engagement.Pharmacodynamic changes found in synapse, immune, vesicle, and lipoprotein biologies.SEQUEL proteomics findings replicated previous trial findings with CT1812.},
}

@article {pmid40547197,
year = {2025},
author = {Yoshimura, T and Osawa, A and Maeshima, S and Ueda, I and Kawamura, K and Kamiya, M and Itoh, N and Arai, H},
title = {Unlocking the Value of Neuropsychological Assessments in Rehabilitation: Perspectives from Persons with Dementia and Their Caregivers.},
journal = {Current therapeutic research, clinical and experimental},
volume = {102},
number = {},
pages = {100781},
pmid = {40547197},
issn = {0011-393X},
abstract = {PURPOSE: Various neuropsychological or cognitive assessments are often conducted before rehabilitation to ascertain patients' function, disability, and environment. However, adequate assessments are not conducted for persons with dementia under the assumption that assessments would burden them. Therefore, this study investigated the perceptions of persons with dementia and their family caregivers regarding cognitive function assessments during hospital rehabilitation and reconsidered the significance of such assessments according to the opinions of those involved.

METHODS: This cross-sectional observational study was conducted over a 3-month period at a hospital-based rehabilitation center. We administered a semi-structured questionnaire to 31 older persons with dementia (13 men and 18 women; mean age [± SD]: 77 [± 5.7] (range: 66-87 years); mean years of education [± SD]: 12 [± 2.3]; (range: 9-16 years); Alzheimer's disease: 15; mild cognitive impairment (MCI): 15; corticobasal degeneration: 1) and 49 family caregiver dyads (24 men and 25 women, mean age [± SD]: 67 [± 11] years; age range: 46-90 years). The data were interpreted by employing descriptive statistics, and the χ[2], Fisher's exact, and Kruskal-Wallis tests.

FINDINGS: Both groups acknowledged the value of neuropsychological assessments, with 94% (95% CI 84.9-100%) of persons with MCI/dementia and 83% (95% CI 73.3-94.0%) of their family caregivers linking them directly to enhanced treatment and care quality. Their positive attitudes were significantly associated with the belief that such evaluations are integral for personalizing and optimizing rehabilitation strategies.

IMPLICATIONS: Most individuals with MCI/dementia and their caregivers value detailed neuropsychological assessments for understanding rehabilitation needs, highlighting the importance of integrating comprehensive evaluations into dementia care. However, the single-center nature of our study limits generalizability. Future research with diverse participants is needed to develop scalable, inclusive rehabilitation strategies.},
}

@article {pmid40546882,
year = {2025},
author = {Mohapatra, TK and Nayak, RR and Ganeshpurkar, A and Tiwari, P and Kumar, D},
title = {Navigating the treatment landscape of Alzheimer's disease: Current strategies and future directions.},
journal = {Ibrain},
volume = {11},
number = {2},
pages = {162-184},
pmid = {40546882},
issn = {2769-2795},
abstract = {Alzheimer's disease (AD), a neurodegenerative disease leading to dementia, lacks a single definitive diagnosis. While current medications only manage symptoms, the ideal treatment would restore cognition. Traditional therapies targeting beta-amyloid haven't yielded significant results, while new approaches target tau protein tangles, protein degradation pathways, inflammation, and neurotrophic factor depletion. Autophagy, a cellular degradation and recycling process, has emerged as a crucial hallmark and contributor to the pathogenesis of AD. Notably, autophagy induction has emerged as a promising therapeutic approach, with inducers like celastrol and caudatin promoting the degradation of toxic protein aggregates. Additionally, innovative drug formulations, such as nanoparticles, are being explored for targeted drug delivery. Research is increasingly focusing on neuroinflammation and developing multi-targeted drugs to address various aspects of AD, potentially leading to preventive strategies in the early stages. This review summarizes the current state and emerging trends in AD drug development.},
}

@article {pmid40546877,
year = {2025},
author = {Wu, W and Yan, Y and Yi, T and Wei, Y and Gao, J and Gong, Q},
title = {Lithocarpus polystachyus Rehd. leaves aqueous extract inhibits learning and memory impairment in Alzheimer's disease rats: Involvement of the SIRT6/NLRP3 signaling pathway.},
journal = {Ibrain},
volume = {11},
number = {2},
pages = {228-244},
pmid = {40546877},
issn = {2769-2795},
abstract = {Alzheimer's disease (AD) is a chronic and progressive neurodegenerative condition that is influenced by multiple factors along with neuroinflammation and oxidative stress. Our previous study proved that Lithocarpus polystachyus Rehd. aqueous extract (sweet tea aqueous extract, STAE) effectively inhibits hydrogen peroxide-induced neuronal cell injury. However, it is not clear whether STAE can protect against AD, and its underlying mechanisms are still uncertain. Therefore, the present study was designed to evaluate the possible behavioral and neurochemical effects of STAE on Aβ 25-35-induced AD rats administered STAE (20, 40, 80 mg/mL) for 14 days. We showed that STAE administration significantly and dose-dependently ameliorated the cognitive deficits in the AD rat models, assessed in the Morris water maze (MWM) test, Y-maze test, and novel object recognition (NOR) test. The results of hematoxylin and eosin (H&E) staining and Nissl staining showed that after treatment with STAE, the pathological damage to the hippocampal CA1, CA3, and dentate gyrus (DG) neurons of rats was significantly improved. Furthermore, STAE dose-dependently inhibited microglia and astrocyte activation in the hippocampus of rats accompanied by increased protein expression of silent mating-type information regulation 2 homolog 6 (SIRT6) and decreased protein expression of nod-like receptor thermal protein domain-associated protein 3 (NLRP3) and its downstream pyroptosis-related genes after following Aβ 25-35. In summary, our findings indicate that STAE effectively inhibits Aβ 25-35-induced learning and memory impairment in rats, and the mechanism is, at least partially, related to the regulation of SIRT6/NLRP3 signaling pathway.},
}

@article {pmid40546798,
year = {2025},
author = {Lai, G and Wu, H and Yang, K and Hu, K and Zhao, W and Chen, X and Li, J and Wang, H and Lv, Z and Xie, G and Wu, X},
title = {Potential Applications of Natural Components of Traditional Chinese Medicine Delivery via Nanoparticle Drug Delivery Systems in the Treatment of Alzheimer's Disease.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {7781-7810},
pmid = {40546798},
issn = {1178-2013},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; Medicine, Chinese Traditional/methods ; Animals ; *Nanoparticle Drug Delivery System/chemistry ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents/administration & dosage/pharmacokinetics ; *Drugs, Chinese Herbal/administration & dosage/pharmacokinetics/chemistry ; *Drug Delivery Systems/methods ; *Nanoparticles/chemistry ; Biological Availability ; },
abstract = {Alzheimer's disease (AD), a primary neurodegenerative disorder, is characterized by amyloid-β plaques and tau hyperphosphorylation-induced neurofibrillary tangles. Current treatments only alleviate symptoms, and Aβ monoclonal antibodies raise safety concerns in clinical use. Natural components (NCs) of Traditional Chinese Medicine (TCM) (eg, curcumin, quercetin, berberine, resveratrol) exhibit multi-target neuroprotective effects in AD, but poor blood-brain barrier (BBB) penetration and low bioavailability limit clinical use. Recent strategies to enhance TCM delivery include NP-based nanoparticle (NP) drug delivery systems (NDDS), structural modifications, and combination therapies. NDDS demonstrate superior performance in enabling brain-targeting delivery via passive (paracellular/transcellular) and active (adsorption-/receptor-/carrier-mediated transcytosis) approaches, improving NCs' stability, controlled release, and bioavailability. With NCs of TCM delivery via NDDS, it is possible to develop intelligent therapeutic systems that combine multi-target regulation with precise drug delivery. This review summarizes the diverse neuroprotective effects of NCs of TCM in AD treatment and discusses the commonly used types of NPs for AD therapy. It particularly focuses on these NCs of TCM delivery via NDDS, covering aspects such as NPs types, fabrication techniques, characteristics, administration routes, and advantages. Finally, the challenges and potential solutions for NCs of TCM were examined, along with comparative advantages and limitations among different NPs and future research directions. Collectively, NCs of TCM delivery via NDDS demonstrate promising therapeutic potential for AD treatment.},
}

*Alzheimer Disease/drug therapy
Humans
Medicine, Chinese Traditional/methods
Animals
*Nanoparticle Drug Delivery System/chemistry
Blood-Brain Barrier/metabolism
Neuroprotective Agents/administration & dosage/pharmacokinetics
*Drugs, Chinese Herbal/administration & dosage/pharmacokinetics/chemistry
*Drug Delivery Systems/methods
*Nanoparticles/chemistry
Biological Availability

@article {pmid40546469,
year = {2025},
author = {Kalochristianaki, S and Vlotinou, P and Bablekos, G and Katsouri, IG and Tsiakiri, A and Georgousopoulou, V and Tsakni, G},
title = {Cost Estimation Analysis of Dementia: A Scope Review.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e84547},
pmid = {40546469},
issn = {2168-8184},
abstract = {Dementia is a progressive neurodegenerative condition, primarily caused by Alzheimer's disease, predominantly affecting elderly individuals. Under these circumstances, dementia care focuses on assisting patients with daily living, either in nursing facilities or at home. The condition imposes substantial economic burdens on patients, caregivers, and healthcare systems, particularly in Europe and North America, where precise cost assessments are essential. This review examines the economic impact of dementia care by integrating diverse cost estimation sources to evaluate the cost-effectiveness of preventive care for high-risk individuals and providing meta-analytic estimates of annual medical, non-medical, and informal care costs per patient, and compares these costs with care effectiveness. The analysis focuses on Europe and the United States, with a greater emphasis on Europe, aiming to encourage further research on preventive strategies and caregiver support. Dementia presents a significant economic challenge globally, driven by rising healthcare costs and an aging population. The disparities between direct and indirect costs in the US and Europe highlight the impact of healthcare systems and cultural practices on dementia care costs. Preventive measures could significantly reduce long-term treatment costs, making them a crucial investment to alleviate future financial burdens.},
}

@article {pmid40546334,
year = {2025},
author = {Cruz, MV and Jamal, S and Sethuraman, SC},
title = {A Comprehensive Survey of Brain-Computer Interface Technology in Health care: Research Perspectives.},
journal = {Journal of medical signals and sensors},
volume = {15},
number = {},
pages = {16},
pmid = {40546334},
issn = {2228-7477},
abstract = {The brain-computer interface (BCI) technology has emerged as a groundbreaking innovation with profound implications across diverse domains, particularly in health care. By establishing a direct communication pathway between the human brain and external devices, BCI systems offer unprecedented opportunities for diagnosis, treatment, and rehabilitation, thereby reshaping the landscape of medical practice. However, despite its immense potential, the widespread adoption of BCI technology in clinical settings faces several challenges. These include the need for robust signal acquisition and processing techniques and optimizing user training and adaptation. Overcoming these challenges is crucial to unleashing the complete potential of BCI technology in health care and realizing its promise of personalized, patient-centric care. This review work underscores the transformative potential of BCI technology in revolutionizing medical practice. This paper offers a comprehensive analysis of medical-oriented BCI applications by exploring the various uses of BCI technology and its potential to transform patient care.},
}

@article {pmid40546257,
year = {2025},
author = {Yu, X and Lu, F and Chen, J and Liu, X and Chen, Q},
title = {A bibliometric analysis of acupuncture treatment and cognitive impairment.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1495191},
pmid = {40546257},
issn = {1664-2295},
abstract = {Cognitive impairment, a prevalent neurological disorder characterized by multisystem dysregulation within the nervous system, has prompted substantial scientific inquiry into complementary therapies. This scientometric investigation systematically examines the evolving bilingual (Chinese-English) research paradigm of acupuncture interventions for cognitive impairment through comparative analysis of 510 publications from the China National Knowledge Infrastructure (CNKI) and 633 articles from Web of Science Core Collection, processed via CiteSpace 6.4.R2. Our multidimensional analysis reveals three principal dimensions: (1) Spatiotemporal evolution demonstrating that scholarly contributions in this domain are predominantly clustered within China. Longitudinal bibliometric analysis demonstrates sustained scholarly productivity in this domain, with annual bilingual (Chinese-English) publication outputs consistently exceeding 40 peer-reviewed articles per annum throughout the 2000-2025 observation window, establishing a robust baseline for continuous knowledge advancement; (2) Network analysis atlas of the research institutions and authors reveals that both research output density and institutional affiliations concentrated in Chinese academic hubs and most authors come from China; (3) Divergent thematic trajectories between linguistic cohorts - Chinese studies emphasize vascular mechanisms, oxidative stress modulation, and pharmacological synergies, whereas English literature prioritizes gut-brain axis interactions, postoperative cognitive recovery, and neuroinflammatory pathways. These findings provide evidence-based insights into acupuncture's therapeutic mechanisms in cognitive impairment while establishing a conceptual framework to guide future translational studies and clinical protocol optimization in integrative neurology.},
}

@article {pmid40546239,
year = {2025},
author = {Liang, J and Dong, X and Yang, J and Hu, N and Luo, X and Cong, S and Chen, J and Zhao, W and Liu, B},
title = {Buyang Huanwu Decoction Modulates the Gut Microbiota-C/EBPβ/AEP Axis to Ameliorate Cognitive Impairment in Alzheimer's Disease Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {6},
pages = {e70480},
doi = {10.1111/cns.70480},
pmid = {40546239},
issn = {1755-5949},
support = {2024yjscx013//Innovative Research Project for Postgraduate Students of Heilongjiang University of Traditional Chinese Medicine/ ; LH2022H059//Natural Science Foundation of Heilongjiang Province of China/ ; LH2023H073//Natural Science Foundation of Heilongjiang Province of China/ ; },
mesh = {Animals ; *Gastrointestinal Microbiome/drug effects/physiology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology/psychology ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; *CCAAT-Enhancer-Binding Protein-beta/metabolism ; Male ; Fecal Microbiota Transplantation ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral disturbances. Buyang Huanwu Decoction (BYHWD), a traditional Chinese herbal formulation, has demonstrated potential neuroprotective effects. This study aims to evaluate the therapeutic impact of BYHWD on cognitive impairments in 3×Tg mice and to investigate its underlying mechanism through modulation of the gut microbiota-C/EBPβ/AEP signaling pathway.

METHODS: In two independent experiments, we assessed the effects of BYHWD and its derived fecal microbiota transplantation (FMT-BYHWD) on behavioral performance, neuropathological alterations, and signaling pathways in 3×Tg mice.

RESULTS: Treatment with BYHWD significantly improved cognitive function in 3×Tg mice and mitigated AD-like pathological changes. By suppressing the C/EBPβ/AEP signaling pathway, BYHWD reduced pathological Aβ plaque deposition, diminished tau hyperphosphorylation, and inhibited the release of pro-inflammatory cytokines. Further analysis revealed that BYHWD restored gut microbiota balance and suppressed the activation of the C/EBPβ/AEP pathway in the hippocampus. Moreover, transplanting FMT-BYHWD from BYHWD-treated mice to germ-free 3×Tg mice also ameliorated their cognitive deficits and AD-like pathology, suggesting that the anti-AD effects of BYHWD are mediated through the gut-brain axis by regulating the interplay between gut microbiota and the C/EBPβ/AEP signaling pathway.

CONCLUSION: This study uncovers the mechanism by which BYHWD improves cognitive deficits and neuropathological changes in 3×Tg mice via the gut-brain axis, mediated by the modulation of the gut microbiota-C/EBPβ/AEP signaling pathway, providing a novel therapeutic strategy for AD.},
}

Animals
*Gastrointestinal Microbiome/drug effects/physiology
*Drugs, Chinese Herbal/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology/psychology
Mice
*Cognitive Dysfunction/drug therapy/metabolism
Mice, Transgenic
*CCAAT-Enhancer-Binding Protein-beta/metabolism
Male
Fecal Microbiota Transplantation
Mice, Inbred C57BL
Signal Transduction/drug effects

@article {pmid40545618,
year = {2025},
author = {Kuzma, A and Valladares, O and Greenfest-Allen, E and Nicaretta, H and Kirsch, M and Ren, Y and Katanic, Z and White, H and Wilk, A and Bass, L and Brettschneider, J and Carter, L and Cifello, J and Chuang, WH and Clark, K and Gangadharan, P and Haut, J and Ho, PC and Horng, W and Iqbal, T and Jin, Y and Keskinen, P and Rose, AL and Moon, MK and Manuel, J and Qu, L and Robbins, F and Saravanan, N and Sha, J and Tate, S and Zhao, Y and , and Cantwell, L and Gardner, J and Chou, SY and Tzeng, JY and Bush, W and Naj, A and Kuksa, P and Lee, WP and Leung, YY and Schellenberg, G and Wang, LS},
title = {NIAGADS: A data repository for Alzheimer's disease and related dementia genomics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70255},
doi = {10.1002/alz.70255},
pmid = {40545618},
issn = {1552-5279},
support = {U24AG041689/AG/NIA NIH HHS/United States ; U54AG052427/AG/NIA NIH HHS/United States ; U01AG032984/AG/NIA NIH HHS/United States ; U01AG058654/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Genomics ; United States ; *Databases, Genetic ; National Institute on Aging (U.S.) ; *Dementia/genetics ; Genome-Wide Association Study ; Information Dissemination ; },
abstract = {The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is the National Institute on Aging-designated national data repository for human genetics research on Alzheimer's disease and related dementias (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis, including whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project and other genotype/phenotype data, encompassing 211,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a Federal Information Security Modernization Act moderate compliant cloud-based platform that fully supports the National Institutes of Health Genomic Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. As a one-stop access portal for Alzheimer's disease (AD) genetics, NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of AD. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is a data repository for the storage of genetics and genomics data. NIAGADS houses data for Alzheimer's disease, related dementias, and healthy aging. NIAGADS offers open and qualified access data and knowledgebases to explore open access data. The Alzheimer's Disease Sequencing Project dataset is the largest Alzheimer's disease and related dementias joint called whole genome sequencing dataset (≈ 58,000 whole genomes).},
}

Humans
*Alzheimer Disease/genetics
*Genomics
United States
*Databases, Genetic
National Institute on Aging (U.S.)
*Dementia/genetics
Genome-Wide Association Study
Information Dissemination

@article {pmid40545559,
year = {2025},
author = {Cummings, J and Cohen, S and Murphy, J and Brothers, HM and Nejati, M and Forrestal, F and de Moor, C and O'Gorman, J and Harrison, J and Jaeger, J and Mummery, CJ and Porsteinsson, AP and Potashman, M and Tian, Y and Yang, L and He, P and Haeberlein, SB},
title = {Evaluation of cognitive, functional, and behavioral effects observed in EMERGE, a phase 3 trial of aducanumab in people with early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70224},
doi = {10.1002/alz.70224},
pmid = {40545559},
issn = {1552-5279},
support = {//Biogen/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/psychology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Male ; Female ; Aged ; Disease Progression ; *Cognition/drug effects ; Treatment Outcome ; Apolipoprotein E4/genetics ; Double-Blind Method ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: In EMERGE (NCT02484547), participants receiving aducanumab had significantly less progression versus placebo on all prespecified clinical endpoints at week 78. Here, we explicate the clinical meaningfulness of these treatment effects by analyzing item-level data and the persistence of treatment benefit.

METHODS: Participants with early Alzheimer's disease (AD) were stratified by apolipoprotein E (APOE) ε4 status and randomized (1:1:1) to receive low- or high-dose aducanumab, or placebo. Prespecified principal component analyses (PCAs) per the Statistical Analysis Plan were followed by post hoc examination of individual domains/items across all five clinical endpoints. Progression analysis assessed reduction in clinical decline.

RESULTS: High-dose aducanumab demonstrated clinically meaningful slowing of progression across clinical endpoints measuring cognition, daily function, and behavioral symptoms. Delay of progression over 18 months was consistent across measures; treatment effects increased over time.

DISCUSSION: Across multiple analyses aducanumab slowed cognitive decline, prolonged functional independence, and attenuated behavioral symptoms in participants with early AD. These outcomes comprise the elements of a clinically meaningful response to treatment.

HIGHLIGHTS: Endpoints in EMERGE assessed different aspects of cognition, daily function, and behavioral symptoms. Treatment benefits were observed across subdomains on all five clinical endpoints. Aducanumab meaningfully slowed disease progression in participants with early AD.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/psychology
*Antibodies, Monoclonal, Humanized/therapeutic use
Male
Female
Aged
Disease Progression
*Cognition/drug effects
Treatment Outcome
Apolipoprotein E4/genetics
Double-Blind Method
Neuropsychological Tests

@article {pmid40544930,
year = {2025},
author = {Geng, D and Liu, A and Yan, Y and Zheng, W},
title = {Intermittent ELF-MF exposure effectively ameliorates pathologic features associated with adult AD mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {149796},
doi = {10.1016/j.brainres.2025.149796},
pmid = {40544930},
issn = {1872-6240},
abstract = {OBJECTIVE: Extremely low frequency magnetic fields (ELF-MF) have been confirmed to have potentially positive effects on Alzheimer's disease (AD). However, the therapeutic effects are influenced by the exposure mode and the pathological process. Currently, there is no optimized treatment plan for the pathological process of AD. This study aims to optimize the exposure mode of ELF-MF to improve the therapeutic effect on AD mice with different degrees of dementia.

METHOD: This study employed 40 Hz, 10mT continuous pulsed ELF-MF stimulation, intermittent (stimulating for 30 min every 12 h) and continuous (stimulating for 60 min every 24 h) ELF-MF exposure. Through calculating various behavioral data, the changes in spatial working memory (SWM) of each group of mice were compared; the time-frequency distribution analysis method was applied to compare the changes in the theta band and gamma band neural oscillations of local field potentials (LFPs) signals in the CA1 region of the hippocampus during the object location task (OLT) of each group of mice; by analyzing the immunofluorescence images of Amyloid-beta 42 (Aβ42) and dynamin-related protein 1 (Drp1) in the hippocampal region of each group of mice, the changes in Aβ42 and Drp1 contents were compared.

RESULTS: ELF-MF stimulation can improve the SWM ability of AD model mice. Among them, intermittent stimulation in the adult group shows a better effect, while continuous stimulation in the aged group is superior. Further LFPs analysis reveals that AD leads to a decrease in theta and gamma frequency band energy in the CA1 area of the hippocampus, while ELF-MF stimulation can significantly enhance its energy. Moreover, in the adult group, the improvement of theta and gamma frequency bands under intermittent stimulation is more obvious, and in the aged group, the improvement of theta frequency band under continuous stimulation is more significant. The results of immunofluorescence detection indicate that ELF-MF stimulation can reduce the abnormal accumulation of Aβ42 and Drp1 in the hippocampus, and the effect of intermittent stimulation in the adult group is more significant.

CONCLUSION: Intermittent ELF-MF exposure may be an effective therapeutic strategy, especially in adult AD mice. This study highlights the potential significance of the ELF-MF exposure pattern in AD treatment and reveals the heterogeneous effects of ELF-MF exposure on the physiological and pathological conditions of AD mice, which has important guiding significance for the formulation of personalized treatment plans in the future.},
}

@article {pmid40544795,
year = {2025},
author = {León-Arcia, K and Pérez-Leal, G and Quintero-Álvarez, H and Zamora-Loyarte, DI and López-Armenteros, M and de la Caridad Sánchez-Quesada, A and Vázquez-Mojena, Y},
title = {Dual Aβ/tau epitope vaccines: a poorly explored strategy for Alzheimer's disease immunotherapy.},
journal = {Vaccine},
volume = {61},
number = {},
pages = {127414},
doi = {10.1016/j.vaccine.2025.127414},
pmid = {40544795},
issn = {1873-2518},
abstract = {Alzheimer's disease (AD) presents a growing public health challenge that urgently requires effective disease-modifying therapies. Active immunotherapy appears to be a promising strategy in AD drug development, offering advantages over passive immunization in terms of prophylactic potential and cost-effectiveness. We systematically reviewed anti-Aβ and anti-tau active immunization strategies over the past 25 years, identifying 577 unique antigenic formulations. Only 3.5 % have progressed to clinical trials, with none yet approved. Notably, only three strategies targeted both Aβ and tau epitopes (Aβ1-11 and tau2-18), despite the potential of multi-target approaches for AD's multifactorial pathology. Given the synergistic role of Aβ and tau in disease progression, dual-target vaccines remain a critical and underinvestigated area with significant therapeutic promise. This review underscores the need to expand research into multi-target immunotherapies that better address AD's complexity, potentially improving prevention and treatment outcomes.},
}

@article {pmid40544750,
year = {2025},
author = {Yang, LY and Hsu, CH and Cheng, YW and Chen, KW and Chou, SC and Chen, YR and Chen, YT and Deng, CR and Chen, IC and Kuo, MF and Wang, KC},
title = {Antroquinonol mitigates Tau hyperphosphorylation, neuronal damage and cognitive impairments in a chronic cerebral ischemia rat model.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {189},
number = {},
pages = {118271},
doi = {10.1016/j.biopha.2025.118271},
pmid = {40544750},
issn = {1950-6007},
abstract = {Chronic cerebral ischemia (CCI) induced hyperphosphorylated Tau has been associated with an increased risk of neurodegenerative disorders such as Alzheimer's and vascular dementia. This study investigated the neuroprotective effects of Antroquinonol (AQ), an ubiquinone derivative from Antrodia camphorata with anti-inflammatory and antioxidant properties. Bilateral internal carotid artery ligation (BICAL) in male Wistar rats and mixed rat primary neuron/glia co-cultures exposed to a hypoxia and hypoglycemia (HH) environment were used as experimental CCI models to investigate the therapeutic effects and mechanisms of AQ. AQ was administered daily at low or high doses for 28 days after BICAL induction. Two and four weeks after BICAL surgery, the functional and cognitive outcomes were evaluated by rotarod test, open field test (OFT), novel object recognition (NOR) and Y-maze test. Nissl, TUNEL, IHC and ICC staining, and Western blot analysis were used to evaluate the effects and underlying mechanisms of AQ in the treatment of CCI. The results showed that both low and high doses of AQ treatment significantly ameliorated motor deficits, anxiety-like behavior, and cognitive impairments in BICAL rats at 2 or 4 weeks post-CCI. Histological and molecular analyses revealed that AQ reduced neuronal injury, microglia activation, apoptosis, and Tau hyperphosphorylation in the cortex and hippocampus regions. We also found that AQ inhibited HH-induced hyperphosphorylation of Tau by modulating protein kinases (p-GSK3β Y216 and p-mTOR), LC3II, and p-NRF2 proteins in cultured cells, suggesting roles in kinase regulation, autophagy, and antioxidation. These findings support AQ as a promise therapeutic candidate for treating CCI-related neurodegenerative disorders.},
}

@article {pmid40544243,
year = {2025},
author = {Mao, R and Shu, S and Sun, M and Chen, J and Hu, M and Ye, L and Xu, S and Jia, J and Shao, W and Bao, X and Xu, Y and Zhu, X},
title = {Edaravone-Dexborneol slows down pathological progression and cognitive decline via inhibiting S100A9 in APPswe/PS1dE9 mice.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {139},
pmid = {40544243},
issn = {1758-9193},
support = {82271480//the National Natural Science Foundation of China/ ; 82471460//the National Natural Science Foundation of China/ ; BK20230053//the Natural Science Foundation of Jiangsu Province of China/ ; BK20231120//the Natural Science Foundation of Jiangsu Province of China/ ; 2022ZD0211800//the STI2030-Major Projects/ ; ZKX22025//Nanjing Medical Science and Technology Development Foundation/ ; },
abstract = {BACKGROUND: Edaravone-Dexborneol (EDB) presents therapeutic effects due to its anti-inflammatory, antioxidant and anti-apoptotic properties, and has been widely used in ischemic stroke. However, the detailed efficacy and potential target of EDB in Alzheimer's disease (AD) are still elusive.

METHODS: Male APPswe/PS1dE9 mice were administered with EDB intraperitoneally from 3.5 to 8 months of age. The cognition of mice was assessed by behavioral tests. Synaptic alternations in the hippocampus were detected by electrophysiology and Golgi staining. β-amyloid (Aβ) pathology was mainly observed by immunofluorescence. Oxidative stress-related indicators were evaluated by dedicated kits, while quantitative PCR and ELISA were used to detect pro-inflammatory factors. Proteomics analysis further identified the potential target of EDB.

RESULTS: EDB was capable of delaying the cognitive decline and ameliorating the synaptic loss in APPswe/PS1dE9 mice. In addition to the anti-inflammation and anti-oxidation effects, EDB treatment mightily ablated the Aβ plaque by promoting microglial phagocytosis. Particularly, we first discovered that EDB could directly bind to S100A9, a pathological molecule that aggravates Aβ pathology and induces oxidative stress and neuroinflammation. EDB inhibited the expression, functional threonine phosphorylation and self-assembly of S100A9.

CONCLUSION: Our results indicate that EDB can improve cognitive function and slow down AD progression, and it may serve as a potential agent for AD and other S100A9-related diseases.},
}

@article {pmid40544093,
year = {2025},
author = {Moon, H and Chen, X and , },
title = {Plasma p-tau217 predicting brain-wide tau accumulation in preclinical AD.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100252},
doi = {10.1016/j.tjpad.2025.100252},
pmid = {40544093},
issn = {2426-0266},
abstract = {BACKGROUND: Recently developed blood test of Alzheimer's disease (AD) has been recognized as a promising alternative to CSF and PET, as it is noninvasive, cost-effective, and more accessible. Particularly, plasma p-tau217 shows high sensitivity in detecting β-amyloid (Aβ) and tau positivity in early AD. However, the potential value of p-tau217 in revealing Aβ and tau distribution and predicting future development has not been studied.

OBJECTIVES: We investigated the dose-response associations between p-tau217 and regional Aβ and tau measured by PET, as well as the longitudinal prediction of p-tau217 for prospective Aβ and tau accumulation measured by longitudinal PET.

DESIGN: Cross-sectional and longitudinal analyses.

SETTING: We used data in Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) study (N = 333) for primary analyses and Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 410) for validation.

PARTICIPANTS: Cognitively unimpaired older adults (N = 333) from A4 study and cognitively unimpaired older adults (N = 222), mild cognitive impairment (N = 114), and dementia (N = 74) from ADNI.

MEASUREMENTS: Plasma p-tau217 was measured using Lilly (A4) and Fujirebio (ADNI) assays. [18-F]Florbetapir PET and [18-F]Flortaucipir PET measured regional Aβ and tau.

RESULTS: Plasma p-tau217 was associated with concurrent Aβ in most cortical regions and tau in temporo-parietal cortices. Longitudinally, p-tau217 predicted brain-wide tau accumulation in widespread cortical regions in preclinical AD, but not Aβ change anywhere.

CONCLUSIONS: Plasma p-tau217 shows dose-response, brain-wide relationships with concurrent Aβ and future tau development in preclinical AD, suggesting its potential in disease trajectory monitoring and large-scale screening for individuals approaching certain biological stages of AD in clinical trials.},
}

@article {pmid40543791,
year = {2025},
author = {Feng, M and Wang, Q and Lei, M and Zhang, D and Yu, Q and Yan, C},
title = {Structural analysis and anti-neuroinflammatory activity of the water-soluble heteropolysaccharide PTTBP-2-2 from Pinellia ternata.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {145268},
doi = {10.1016/j.ijbiomac.2025.145268},
pmid = {40543791},
issn = {1879-0003},
abstract = {Neuroinflammation is closely linked to Alzheimer's disease, where the deposition of amyloid-beta activates microglia, triggering multiple processes that lead to neuronal damage and cognitive decline. However, studies have shown that water extract of Pinellia ternata can improve cognitive function and reduce inflammatory response in the brain injury of mice. Herein, a water-soluble polysaccharide, PTTBP-2-2. with a molecular weight of 11.7 kDa, consisting of D-Glc, D-Gal, D-Xyl, and L-Ara, was isolated from P. ternata. Methylation analysis, partial acid hydrolysis, and nuclear magnetic resonance revealed that the of PTTBP-2-2 backbone consisted of →4)-α-D-Glcp-(1→, →4,6)-α-D-Glcp-(1→, and →6)-α-D-Galp-(1 → residues, with side chains substituted at O-2, O-3, and O-6 positions of →4)-α-D-Glcp-(1→. In vitro experiments demonstrated that PTTBP-2-2 significantly reduced nitrous oxide levels in BV2 microglia cells and suppressed the expression of pro-inflammatory genes, including COX2, iNOS, TNF-α, IL-1β, and IL-6. These factors are key mediators of neuroinflammation. Mechanistic investigations revealed that the anti-neuroinflammatory activity of PTTBP-2-2 was mediated through the regulation of NF-κB and Nrf2/HO-1 signaling pathways. Overall, PTTBP-2-2 shows potential as a therapeutic agent for the treatment of neuroinflammation.},
}

@article {pmid40543641,
year = {2025},
author = {Chen, X and Cao, YG and Hao, FX and Liu, YL and Chi, FG and Niu, Y and Lu, D and Zhao, BX and Chen, L and Zheng, XK and Feng, WS},
title = {Alkaloids from the tubers of Pinellia pedatisecta.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114597},
doi = {10.1016/j.phytochem.2025.114597},
pmid = {40543641},
issn = {1873-3700},
abstract = {Nine undescribed alkaloids (1, 3, 4, 7, 8 and 10-13) and four undescribed natural products (2, 5, 6 and 9), together with eight known components, were isolated from the tubers of Pinellia pedatisecta Schott. Their structures were elucidated based on spectroscopic data, Rh2(OCOCF3)4-induced ECD spectral analysis, DP4+ analysis, ECD analysis and interpretation of their optical rotation data. The protective effects of all compounds against Aβ25-35-induced PC-12 cell injury were tested by MTT method, and the results indicated that compounds 1, 2, 5-10 and 16-20 exhibited obviously protective effects. In addition, the action mechanisms of compounds 2 and 5 were investigated by flow cytometry and cellular immunofluorescence, and the results indicated that compounds 2 and 5 ameliorated Aβ25-35-induced PC-12 cell injury via the NMDAR/p-CamK II/PKG signaling pathway. This study provided experimental basis for researching the chemical composition of P. pedatisecta and developing natural medicines for the treatment of Alzheimer's disease in the future.},
}

@article {pmid40543640,
year = {2025},
author = {Chen, X and Cao, YG and Chi, FG and Liu, YL and Ye, KL and Zheng, XK and Feng, WS},
title = {Norsesquiterpenes from the stems and leaves of Pinellia pedatisecta Schott.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114590},
doi = {10.1016/j.phytochem.2025.114590},
pmid = {40543640},
issn = {1873-3700},
abstract = {A chemical investigation of the stems and leaves of Pinellia pedatisecta Schott afforded forty norsesquiterpenes, including eleven undescribed compounds (1-6, 10-13, and 23) and twenty-nine known analogues. Their structures were elucidated using detailed spectroscopic and comparative literature data analysis. The Mo2(OAc)4-induced ECD spectral analysis, DP4+ and ECD analysis were used to determine the absolute configuration of undescribed isolates. In addition, the results of the bioactivity evaluation indicated that components 3-6, 8-10, 12, 14, 15, 17-19, 21-22, 25-29, 33, and 39 significantly improved Aβ25-35-induced PC-12 cell damage. The network pharmacology results showed that STAT3, NFKB1, HIF1A, EGFR, CASP3 were the correlated targets of compounds 3-6, 10, and 12 against AD, with Ras, PI3K-Akt, and MAPK as the potential signaling pathways. This study provided experimental basis for the treatment of Alzheimer's disease and we will further explore mechanisms in cells and mice to find accurate targets and pathways in the future.},
}

@article {pmid40542938,
year = {2025},
author = {Cherait, A and Xifró, X and Reglodi, D and Vaudry, D},
title = {More Than Three Decades After Discovery of the Neuroprotective Effect of PACAP, What Is Still Preventing Its Clinical Use?.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {3},
pages = {80},
pmid = {40542938},
issn = {1559-1166},
abstract = {Discovered in 1989, pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with strong neuroprotective properties, as shown in various neurodegenerative preclinical models of Parkinson, Alzheimer, or Huntington diseases. PACAP neuroprotection has also been reported in animal models of cerebral ischemia and traumatic brain injury. The neuroprotective effect of PACAP occurs through its capacity to modulate most of the multiphasic aspects of neuronal diseases, such as oxidative stress, neuronal cell death, and inflammation. However, more than three decades after its discovery, and although PACAP neurotrophic and neuroprotective activities have now been largely documented, its clinical use is still awaited. Thus, the aim of this manuscript is to discuss the main reasons which limit the use of PACAP as a therapeutic agent for the treatment of neuronal diseases. To achieve this objective, an opinion survey has been conducted among experts in the field of PACAP, and a bibliographic investigation was carried out.},
}

@article {pmid40542726,
year = {2025},
author = {Lv, Y and Song, X and He, J and Jiang, X and Lu, L and Fan, M and Guo, Z and Zhang, C and Xie, Y},
title = {3-Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer's Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c00502},
pmid = {40542726},
issn = {1520-4804},
abstract = {The challenges in the current treatment landscape for Alzheimer's disease (AD) underscore the urgent need for novel therapeutic strategies targeting multiple pathological pathways. Recent studies have implicated iron in ROS-dependent neuronal injury through ferroptosis. Additionally, overexpression of monoamine oxidase B (MAO-B) induces oxidative stress and decreases cognitive function. In this study, we presented the novel dual inhibitors of ferroptosis and MAO-B for AD management, aiming to address both the symptomatic and neurodegenerative aspects of this disease. Compound 21d emerged as a promising candidate, exhibiting potent and selective MAO-B inhibitory activity (IC50 = 87.47 nM, SI > 229), as well as excellent antiferroptosis activity through modulation of the iron metabolic pathway and GSH-GPX4 axis in vitro. Importantly, 21d normalized cognitive and memory impairments in a 3×Tg (APP/Tau/Ps1) AD mouse model and reduced levels of AD-related proteins, including amyloid precursor protein and phosphorylated Tau protein, in the brains of AD mice.},
}

@article {pmid40542704,
year = {2025},
author = {Aly, HF and Fouad, GI and Khalil, WKB and Kamel, NN and El-Rigal, NS and Ahmed, KA and Taha, DA and Shalaby, MB and Abd El-Karim, SS and Abou Baker, DH and Rizk, MZ},
title = {Evaluating the therapeutic efficacy of a Benzofuran-Enaminone derivative for the management of Alzheimer's disease (AD)-like pathology in rats through regulating the expression of apoptosis and AD-related genes.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/01616412.2025.2520021},
pmid = {40542704},
issn = {1743-1328},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder. There is currently no promising cure for AD; the available treatments can only alleviate the symptoms.

OBJECTIVES: The Benzofuran-Enaminone derivative '(E)-1-(benzofuran-2-yl)-3-((2-hydroxyphenyl)amino)prop-2-en-1-one (5)' was synthesized as a potential anti-AD candidate in Aluminum chloride (AlCl3)-induced AD in rats.

METHODS: In vivo and in vitro acute and chronic studies were conducted to examine the potential toxicity, as well as the antioxidant and anti-acetylcholinesterase (AChE) activities of compound 5. Then, rats were divided into four groups: (1) negative control; (2) AD-induced rats; (3) AD-induced rats treated with compound 5; and (4) AD-induced rats treated with Donepezil. Behavioral, biochemical, and molecular investigations were conducted. The expression of insulin 1 gene, apoptotic genes, and the AD-related genes were estimated.

RESULTS: The selected dose of compound 5 (10 mg/kg) was based on an acute toxicity test, then it was applied for a chronic study for 1 month; no toxicological features were stimulated. In vitro, compound 5 demonstrated antioxidant and anti-AChE activities. The expression of apoptotic genes (Bcl-2, Bax, and Caspase-3), AD-related genes (Amyloid precursor protein (APP) and Tau), and the insulin 1 gene were altered in AD-induced rats versus control rats. Treatment of AD rats with compound 5 counteracted the AlCl3-induced neurotoxicity.

CONCLUSION: This study could be regarded as an initial step in drug discovery for testing this new chemical entity as a potent anti-AD therapeutic agent.},
}

@article {pmid40542425,
year = {2025},
author = {Liu, Y and Hong, T and Lv, M and Guo, X and Zhang, P and Yan, A and Wei, W},
title = {Delphinidin attenuates cognitive deficits and pathology of Alzheimer's disease by preventing microglial senescence via AMPK/SIRT1 pathway.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {138},
pmid = {40542425},
issn = {1758-9193},
support = {82302417//National Natural Science Foundation of China/ ; 82201565//National Natural Science Foundation of China/ ; QMRC2203//the Qingmiao Talent Program of Huadong Hospital/ ; 24ZR1420800//Natural Science Foundation of Shanghai Municipality/ ; 21YF1411600//Shanghai Sailing Program/ ; HDLC2022003//the Investigator Initiated Research Projects of Huadong Hospital/ ; SHDC22022304//the Shanghai Hospital Development Center Foundation/ ; },
abstract = {BACKGROUND: Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy.

OBJECTIVES: This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms.

METHODS: We employed APP/PS1 mice, naturally aged mice, and an in vitro model using Aβ42-induced senescent BV2 microglia. Delphinidin's effects were evaluated through assessments of cognitive function, synaptic integrity (synapse loss), Aβ plaque burden, senescent microglia gene signatures, and cellular senescence markers (including senescence-associated β-galactosidase activity, SASP factor expression, oxidative stress, and cyclin p21/p16 levels). Mechanistic studies involved analyzing the AMPK/SIRT1 signaling pathway, testing direct delphinidin-SIRT1 interaction, and using the AMPK inhibitor Compound C.

RESULTS: Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, Aβ peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, cyclin p21 and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. In vitro, delphinidin treatment attenuated cell senescence induced by Aβ42 in BV2 microglia cells. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence.

CONCLUSION: Our study reveals for the first time that delphinidin effectively improved cognitive deficits, alleviated synapse loss and Aβ pathology in APP/PS1 mice by mitigating microglial senescence. These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.},
}

@article {pmid40541947,
year = {2025},
author = {Guan, P and Ruan, Q and Li, J and Xi, M and Qi, W and Ko, KI and Ni, J},
title = {Ferroptosis in periodontitis: mechanisms, impacts, and systemic connections.},
journal = {Cell death discovery},
volume = {11},
number = {1},
pages = {283},
pmid = {40541947},
issn = {2058-7716},
support = {2025A1515012494//Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)/ ; A2022522//Guangdong Medical Research Foundation (Guangdong Province Medical Research Foundation)/ ; B2022262//Guangdong Medical Research Foundation (Guangdong Province Medical Research Foundation)/ ; A223450//Guangdong Medical Research Foundation (Guangdong Province Medical Research Foundation)/ ; },
abstract = {Periodontitis is a chronic inflammatory disease initiated by plaque microorganisms, with the regulatory mechanisms of its progression being a primary research focus. Ferroptosis, a unique form of cell death driven by iron-dependent lipid peroxidation, has been increasingly recognized for its crucial role in modulating chronic inflammation. This study focused on the molecular mechanisms by which plaque microorganisms and the inflammatory microenvironment trigger ferroptosis in periodontal cells, elucidating how ferroptosis in these cells promotes periodontitis progression. Additionally, the potential exacerbation of periodontitis through ferroptosis in systemic diseases such as Alzheimer's disease, nonalcoholic steatohepatitis, chronic obstructive pulmonary disease, and type 2 diabetes is discussed. This review aims to provide new theoretical foundations and strategies for the treatment of periodontitis.},
}

@article {pmid40541595,
year = {2025},
author = {Alkhammash, A and Alotaibi, G},
title = {Epigenetic Reprogramming as a Therapeutic Strategy for Neurodegenerative Diseases: A Complex and Novel Approach.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177853},
doi = {10.1016/j.ejphar.2025.177853},
pmid = {40541595},
issn = {1879-0712},
abstract = {Epigenetic reprogramming has emerged as a promising therapeutic strategy for neurodegenerative diseases by targeting reversible gene expression changes without altering the underlying DNA sequence. This review explores key epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, that contribute to neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Pharmacological interventions such as DNA methylation modulators, histone deacetylase (HDAC) inhibitors, and non-coding RNA therapies have shown potential in restoring normal gene function. Advanced approaches, including CRISPR-dCas9 epigenetic editing, synthetic transcription factors (STFs), and Yamanaka factor-mediated cellular rejuvenation, offer precise control over disease-associated gene expression. Despite these advancements, several challenges and controversies remain, including off-target effects, delivery limitations, long-term safety concerns, and ethical implications. Emerging research focuses on multi-target combination therapies, integrating epigenetic interventions with stem cell therapy, immune checkpoint inhibitors, and AI-driven precision medicine. Future directions involve the development of non-invasive drug delivery systems, AI-powered biomarker discovery, and personalized epigenome-based treatments to enhance therapeutic outcomes. As research advances, epigenetic reprogramming holds the potential to revolutionize neurodegenerative disease treatment, providing more effective, individualized, and disease-modifying interventions.},
}

@article {pmid40541584,
year = {2025},
author = {Tao, X and Wang, L and Gong, W},
title = {Untargeted metabolomics reveals the mechanisms of luteolin and exercise combination treatment against cognitive impairments in AD mice through modulating autophagy.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110011},
doi = {10.1016/j.jnutbio.2025.110011},
pmid = {40541584},
issn = {1873-4847},
abstract = {BACKGROUND: Alzheimer's disease (AD) yields a dramatic burden on patients and their families, with no complete cure yet. Our group has previously found that AD-related cognitive impairment (ARCI) could be alleviated after luteolin and exercise combination treatment (Lut + Exe), but the potential mechanisms require further exploration.

PURPOSE: This work used untargeted metabolomics to uncover the mechanisms Lut + Exe protects against ARCI.

METHODS: Utilizing an Aβ1-42-oligomers-induced AD model, the Morris water maze (MWM) test was performed. Metabolomics of plasma was performed to identify differential metabolites. KEGG and MetaboAnalyst were used to enrich the metabolic pathways. Then, the autophagy inhibitor chloroquine (CQ) was utilized to verify the potential role of autophagy in the Lut+ Exe efficacy against ARCI.

RESULTS: The results showed that Lut + Exe alleviated the ARCI in mice. The in-depth analysis showed that Lut + Exe could significantly affect purine metabolism, retinol metabolism, thiamine metabolism, histidine metabolism, and cysteine and methionine metabolism, indicating that the energy metabolism disorder was alleviated. Based on the close relationship between autophagy and energy metabolism, further study found that Lut + Exe could reverse the significant reduction of key autophagy proteins of AD model mice, while the effects of it on the MWM performance and neurogenesis of AD model mice could be blocked by CQ.

CONCLUSION: This study reveals the crucial role of autophagy in the mechanisms of Lut + Exe against ARCI using untargeted metabolomics. Our work provides a novel paradigm to promote the use of combination treatment in curing AD.},
}

@article {pmid40541317,
year = {2025},
author = {Frecska, E and Kovács, A and Szabo, A},
title = {The protective effect of DMT against neurodegeneration.},
journal = {International review of neurobiology},
volume = {181},
number = {},
pages = {395-420},
doi = {10.1016/bs.irn.2025.04.010},
pmid = {40541317},
issn = {2162-5514},
abstract = {This paper explores the therapeutic potential of DMT in neuroprotective strategies, particularly concerning ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Besides its potent serotonin receptor actions, DMT is also an endogenous agonist of the sigma-1 receptor (Sig-1R). Sigma receptors are a unique family of proteins with high expression in the brain and spinal cord and have been involved in the etiology, symptom course and treatment of several central nervous system disorders. Our previous theoretical and experimental work strongly suggest that targeting sigma (and serotonin) receptors via DMT may be particularly useful for treatment in a number of neurological conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. In this article, we briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of our previous preclinical (in vitro and in vivo) DMT studies aiming at mitigating IRI and related cellular neuropathologies. We conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest. The multiple neuroprotective mechanisms facilitated by DMT may position it as a model molecule for developing pharmacological treatments for neurodegenerative disorders.},
}

@article {pmid40541177,
year = {2025},
author = {Habich, C and Kowalski, A and Wachter, A and Heimann, MJ and Wolf, M and Kummer, MP and Nicolaisen, N and Sliwinski, C and Reinhardt, L and Heil, V and Lange, T and Untucht, C and Miller, LN and Korffmann, J and Geist, D and Schöndorf, D and Lee, H and Bahnassawy, L and Mielich-Süss, B and Brennan, MS and Wilkens, R and Röwe, J and Weidling, I and Rudolf, R and Hafner, M and Manos, JD and Cik, M and Reinhardt, P},
title = {BMP, MEK, and WNT inhibition with NGN2 expression for rapid generation of hiPSC-derived neurons amenable to regional patterning.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102539},
doi = {10.1016/j.stemcr.2025.102539},
pmid = {40541177},
issn = {2213-6711},
abstract = {Human induced pluripotent stem cells (hiPSCs) are a promising tool for studying neurological diseases and developing therapies for neurodegenerative diseases. Differentiation of hiPSCs into neurons can be achieved by dual SMAD inhibition (dSMADi) or by induced neurogenin 2 (NGN2) overexpression ("iNGN2"). Starting directly from hiPSCs, iNGN2 shortens the time to a neuronal stage but leads to neurons partially resembling peripheral or posterior fates while dSMADi more faithfully recapitulates telencephalic development. To modify the iNGN2 approach, we applied an accelerated induction paradigm that is dependent on the inhibition of BMP, MEK, and WNT pathways ("BMWi"), to commit hiPSCs into a telencephalic fate before iNGN2. The resulting neurons showed strong expression of telencephalic markers, with decreased levels of peripheral and posterior marker genes compared to iNGN2 alone. The resulting telencephalic neurons are suitable for a tau aggregation assay. Furthermore, we could demonstrate that during BMWi treatment, the cells are amenable to additional regional patterning cues. This allowed the generation of neurons from different regions of the CNS and peripheral nervous system (PNS), which will significantly facilitate in vitro modeling of a range of neurodevelopmental and neurodegenerative disorders.},
}

@article {pmid40541115,
year = {2025},
author = {Pinheiro, PSM and de Chirico, F and Loi, M and Trazzi, S and Ciani, E and Rodrigues, DA and Alves, MA and Lima, LM and Milelli, A and Monti, B and Manssour Fraga, CA and Bolognesi, ML},
title = {Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {296},
number = {},
pages = {117868},
doi = {10.1016/j.ejmech.2025.117868},
pmid = {40541115},
issn = {1768-3254},
abstract = {The discovery of new therapeutic agents for the treatment of neurodegenerative diseases-particularly Alzheimer's disease (AD) -remains one of the most challenging areas in medicinal chemistry. Given the multifactorial nature of these disorders, the rational design of multitarget-directed ligands (MTDLs) is gaining increasing attention, underscoring the importance of exploring novel target combinations. In this study, we report the design of the first-in-class multitarget compounds that function as dual GPR40 agonists and HDAC6 inhibitors-a novel strategy aimed at modulating neuroinflammation in AD. Among them, compound 4e exhibited potent activity, with an EC50 of 22 nM for GPR40 activation and an IC50 of 73 nM for HDAC6 inhibition. This balanced dual profile was corroborated in cell-based assays, where compound 4e significantly increased acetylated tubulin and ERK phosphorylation levels in SH-SY5Y cells. Furthermore, compound 4e demonstrated immunomodulatory effects on microglia, highlighting its potential as a chemical starting point for targeting neuroinflammation and, ultimately, neurodegeneration.},
}